Riccardo Petrelli | Università degli studi di Camerino UNICAM (original) (raw)

Papers by Riccardo Petrelli

Research paper thumbnail of Isofuranodiene, a Natural Sesquiterpene Isolated from Wild Celery (Smyrnium olusatrum L.), Protects Rats against Acute Ischemic Stroke

Pharmaceuticals

The myrrh-like furanosesquiterpene isofuranodiene (IFD) is the main constituent of wild celery (S... more The myrrh-like furanosesquiterpene isofuranodiene (IFD) is the main constituent of wild celery (Smyrnium olusatrum L., Apiaceae), an overlooked vegetable that was cultivated during the Roman Empire. In the present study, we investigated the protective effects of IFD pre-treatment against oxidative stress and inflammatory response in an animal model of ischemic stroke. IFD was isolated by the crystallization of Smyrnium olusatrum essential oil, and its structure and purity were confirmed by NMR and HPLC analyses. Acute pre-treatment of IFD (10 mg/kg i.p.) significantly reduced the levels of the inflammatory cytokines IL-1β and TNF-α, the expression of pNF-κB/NF-κB, and the lipid peroxidation indicator MDA. Finally, IFD boosted a faster recovery and better scores in grid-walking and modified neurological severity scores (mNSS) tests. Taken together, these findings indicate IFD as a promising lead compound for the discovery of new treatments of brain ischemia.

Research paper thumbnail of Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure

Small molecules that act on multiple biological targets have been proposed to combat the drug res... more Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed.

Research paper thumbnail of 5'-C-Ethyl-tetrazolyl-N(6)-Substituted Adenosine and 2-Chloro-adenosine Derivatives as Highly Potent Dual Acting A1 Adenosine Receptor Agonists and A3 Adenosine Receptor Antagonists

Journal of medicinal chemistry, Jan 12, 2015

A series of N(6)-substituted-5'-C-(2-ethyl-2H-tetrazol-5-yl)-adenosine and 2-chloro-adenosine... more A series of N(6)-substituted-5'-C-(2-ethyl-2H-tetrazol-5-yl)-adenosine and 2-chloro-adenosine derivatives was synthesized as novel, highly potent dual acting hA1AR agonists and hA3AR antagonists, potentially useful in the treatment of glaucoma and other diseases. The best affinity and selectivity profiles were achieved by N(6)-substitution with a 2-fluoro-4-chloro-phenyl- or a methyl- group. Through an in silico receptor-driven approach, the molecular bases of the hA1- and hA3AR recognition and activation of this series of 5'-C-ethyl-tetrazolyl derivatives were explained.

Research paper thumbnail of Stereoselective Synthesis of Nicotinamide β-Riboside and Nucleoside Analogues

ChemInform, 2004

Stereoselective Synthesis of Nicotinamide β-Riboside and Nucleoside Analogues. -The key elements ... more Stereoselective Synthesis of Nicotinamide β-Riboside and Nucleoside Analogues. -The key elements of the stereoselective synthesis of nicotinamide and nicotinic acid β-ribosides (V) involve the formation of silylated nicotinic bases and their coupling with protected sugars (II) under Vorbruggen's conditions in the presence of a catalytic amount of Tms-O-Tf. This method, carried out under controlled conditions, provide only the β-anomers (IV). Basic hydrolytic deblocking of (IV) at low temperature minimizes cleavage of the glycosidic linkage to afford the desired targets (V) as white solids after purification. -(FRANCHETTI*, P.; PASQUALINI, M.; PETRELLI, R.; RICCIUTELLI, M.; VITA, P.; CAPPELLACCI, L.; Bioorg. Med.

Research paper thumbnail of From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: Synthesis and biological evaluation of valproic esters of 3′-C-methyladenosine

Bioorganic & Medicinal Chemistry Letters, 2014

We synthesized a series of serum-stable covalently linked drugs derived from 3 0 -C-methyladenosi... more We synthesized a series of serum-stable covalently linked drugs derived from 3 0 -C-methyladenosine (3 0 -Me-Ado) and valproic acid (VPA), which are ribonucleotide reductase (RR) and histone deacetylase (HDAC) inhibitors, respectively. While the combination of free VPA and 3 0 -Me-Ado resulted in a clear synergistic apoptotic effect, the conjugates had lost their HDAC inhibitory effect as well as the corresponding apoptotic activity. Two of the analogs, 2 0 ,5 0 -bis-O-valproyl-3 0 -C-methyladenosine (A160) and 5 0 -O-valproyl-3 0 -C-methyladenosine (A167), showed promising cytotoxic activities against human hematological and solid cancer cell lines. A167 was less potent than A160 but had interesting features as an RR inhibitor. It inhibited RR activity by competing with ATP as an allosteric effector and concomitantly reduced the intracellular deoxyribonucleoside triphosphate (dNTP) pools. A167 represents a novel lead compound, which in contrast to previously used RR nucleoside analogs does not require intracellular kinases for its activity and therefore holds promise against drug resistant tumors with downregulated nucleoside kinases.

Research paper thumbnail of Synthesis, biological evaluation, and molecular modeling of ribose-modified adenosine analogues as adenosine receptor agonists

Journal of Medicinal Chemistry, 2005

A number of 3′-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA... more A number of 3′-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA, 2′-Me-CCPA, NECA, and IB-MECA was synthesized to further investigate the subdomain of the receptor that binds the ribose moiety of the ligands. Affinity data at A 1 , A 2A , and A 3 receptors in bovine brain membranes showed that the 3′-C-modification in adenosine resulted in a decrease of the affinity at all three receptor subtypes. When this modification was combined with N 6 -substitution with groups that induce high potency and selectivity at A 1 receptor, the affinity and selectivity were increased. However, all 3′-C-methyl derivatives proved to be very less active than the corresponding 2′-C-methyl analogues. The most active compound was found to be 3′-Me-CPA which displayed a K i value of 0.35 µM at A 1 receptor and a selectivity for A 1 vs A 2A and A 3 receptors higher than 28-fold. 2′-Me-CCPA was confirmed to be the most selective, high affinity agonist so far known also at human A 1 receptor with a K i value of 3.3 nM and 2903-and 341-fold selective vs human A 2A and A 3 receptors, respectively. In functional assay, 3′-Me-CPA, 3′-Me-CCPA, and 2-Cl-3′-Me-IB-MECA inhibited forskolin-stimulated adenylyl cyclase activity with IC 50 values ranging from 0.3 to 4.9 µM, acting as full agonists. A rhodopsin-based model of the bovine A 1 AR was built to rationalize the higher affinity and selectivity of 2′-C-methyl derivatives of N 6 -substituted-adenosine compared to that of 3′-Cmethyl analogues. In the docking exploration, it was found that 2′-Me-CCPA was able to form a number of interactions with several polar residues in the transmembrane helices TM-3, TM-6, and TM-7 of bA 1 AR which were not preserved in the molecular dynamics simulation of 3′-Me-CCPA/bA 1 AR complex.

Research paper thumbnail of Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice

Experimental Neurology, 2014

Dopamine Adenosine Substantia nigra pars reticulata Levodopa Dyskinesia Mice GABAergic terminals ... more Dopamine Adenosine Substantia nigra pars reticulata Levodopa Dyskinesia Mice GABAergic terminals γ-Aminobutyric acid A receptor (GABA A R)-mediated postsynaptic currents were recorded in brain slices from substantia nigra pars reticulate neurons. The selective adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) in the presence of the dopamine D1 receptor agonist SKF 38393 (SKF) and phosphodiesterase 10A inhibitors (papaverine or AE90074). Under these conditions, DPCPX also increased the amplitude of evoked IPSCs (eIPSCs). The effect of DPCPX was also examined in a mouse model of Parkinson's disease (PD), generated by unilateral denervation of the dopaminergic input to the striatum. In this model, SKF alone was sufficient to increase sIPSCs frequency and eIPSCs amplitude, and these effects were not potentiated by DPCPX. To confirm a depressive effect of A1Rs on the synaptic release of GABA we used the selective A1R agonist 5′-chloro-5′-deoxy-N 6 -(±)-(endo-norborn-2-yl)adenosine (5′Cl5′d-(±)-ENBA) which has limited peripheral actions. We found that 5′Cl5′d-(±)-ENBA decreased sIPSCs frequency, without affecting their amplitude, and decreased eIPSCs amplitude. Importantly, in the PD mouse model, 5′Cl5′d-(±)-ENBA prevented the increase in sIPSC frequency and eIPSC amplitude produced by SKF. Since exaggerated DA transmission along the striato-nigral pathway is involved in the motor complications (e.g. dyskinesia) caused by prolonged and intermittent administration of L-DOPA, we examined the effect of A1R activation in mice with unilateral DA denervation. We found that 5′Cl5′ d-(±)-ENBA, administered in combination with L-DOPA, reduced the development of abnormal involuntary movements. These results indicate the potential benefit of A1R agonists for the treatment of L-DOPA-induced dyskinesia and hyperkinetic disorders providing a mechanistic framework for the study of the interaction between DA and adenosine in the striatonigral system.

Research paper thumbnail of Novel Inhibitors of Inosine Monophosphate Dehydrogenase in Patent Literature of the Last Decade

Recent Patents on Anti-Cancer Drug Discovery, 2013

Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthe... more Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthesis of guanine nucleotides, has received considerable interest in recent years as an important target enzyme, not only for the discovery of anticancer drugs, but also for antiviral, antiparasitic, and immunosuppressive chemotherapy. The field of IMPDH inhibitor research is highly important for providing potential therapeutics against a validated target for disease intervention. This patent review examines the chemical structures and biological activities of recently reported IMPDH inhibitors. Patent databases SciFinder and Espacenet and Delphion were used to locate patent applications that were published between January 2002 and July 2012, claiming chemical structures for use as IMPDH inhibitors. From 2002 to 2012, around 47 primary patent applications have claimed IMPDH inhibitors, which we analyzed by target and applicant. The level of newly published patent applications covering IMPDH inhibitors remains high and a diverse range of scaffolds has been claimed.

Research paper thumbnail of Synthesis and Antitumor Activity of a Heterodinucleotide of BVDU and Gemcitabine

Nucleosides, Nucleotides and Nucleic Acids, 2008

A heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5′,5′-pyrophospate bridg... more A heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5′,5′-pyrophospate bridge (BVDUp2dFdC) has been synthesized and evaluated as antitumor agent against AH13 rat sarcoma cells. BVDUp2dFdC showed a cytotoxicity similar to that of Gemcitabine.

Research paper thumbnail of Antitumor Activity of C -Methyl-β- d -ribofuranosyladenine Nucleoside Ribonucleotide Reductase Inhibitors

Journal of Medicinal Chemistry, 2005

A series of adenosine derivatives substituted at the 1′-, 2′-, or 3′-position of the ribose ring ... more A series of adenosine derivatives substituted at the 1′-, 2′-, or 3′-position of the ribose ring with a methyl group was synthesized and evaluated for antitumor activity. From this study 3′-C-methyladenosine (3′-Me-Ado) emerged as the most active compound, showing activity against human myelogenous leukemia K562, multidrug resistant human leukemia K562IU, human promyelocytic leukemia HL-60, human colon carcinoma HT-29, and human breast carcinoma MCF-7 cell lines with IC 50 values ranging from 11 to 38 µM. Structure-activity relationship studies showed that the structure of 3′-Me-Ado is crucial for the activity. Substitution of a hydrogen atom of the N 6 -amino group with a small alkyl or cycloalkyl group, the introduction of a chlorine atom in the 2-position of the purine ring, or the moving of the methyl group from the 3′-position to other ribose positions brought about a decrease or loss of antitumor activity. The antiproliferative activity of 3′-Me-Ado appears to be related to its ability to deplete both intracellular purine and pyrimidine deoxynucleotides through ribonucleotide reductase inhibition.

Research paper thumbnail of Ribose-Modified Purine Nucleosides as Ribonucleotide Reductase Inhibitors. Synthesis, Antitumor Activity, and Molecular Modeling of N 6 -Substituted 3′- C -Methyladenosine Derivatives

Journal of Medicinal Chemistry, 2008

A series of cycloalkyl, bicycloalkyl, aryl, and heteroaryl N 6 -substituted derivatives of the an... more A series of cycloalkyl, bicycloalkyl, aryl, and heteroaryl N 6 -substituted derivatives of the antitumor agent 3′-C-methyladenosine (3′-Me-Ado), an inhibitor of the R Rnr1 subunit of mammalian ribonucleotide reductase (RR), were synthesized. The cytotoxicity of these compounds was evaluated against a panel of human leukemia and carcinoma cell lines and compared to that of some corresponding N 6 -substituted adenosine analogues. N 6 -cycloalkyl-3′-C-methylribonucleosides 2-7 and N 6 -phenyl analogue 8 were found to inhibit the proliferation of K562 leukemia cells. N 6 -(()-endo-2-norbornyl-3′-C-methyladenosine (7) was found to be the most cytotoxic compound, with GI 50 values slightly higher than that of 3′-Me-Ado against K562 and carcinoma cell lines and 2.7 fold higher cytotoxicity against human promyelocytic leukemia HL-60 cells. The SAR study confirms that an unsubstituted N 6 -amino group is essential for optimal cytotoxicity of 3′-Me-Ado against both K562 and carcinoma cell lines. Computational studies, carried out on the eukaryotic R subunit (Rnr1) of RR from Saccharomyces cereVisiae were performed to rationalize the observed structure-activity relationships.

Research paper thumbnail of N 6 -Cycloalkyl- and N 6 -Bicycloalkyl- C 5′( C 2′)-modified Adenosine Derivatives as High-Affinity and Selective Agonists at the Human A 1 Adenosine Receptor with Antinociceptive Effects in Mice

Journal of Medicinal Chemistry, 2009

To further investigate new potent and selective human A 1 adenosine receptor agonists, we have sy... more To further investigate new potent and selective human A 1 adenosine receptor agonists, we have synthesized a series of 5′-chloro-5′-deoxy-and 5′-(2-fluorophenylthio)-5′-deoxy-N 6 -cycloalkyl(bicycloalkyl)-substituted adenosine and 2′-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A 1 , A 2A , A 2B , and A 3 adenosine receptors. In the series of N 6 -cyclopentyl-and N 6 -(endo-norborn-2-yl)adenosine derivatives, 5′-chloro-5′-deoxy-CPA (1) and 5′-chloro-5′-deoxy-(()-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA 1 vs the other human receptor subtypes. The higher affinity and selectivity of 5′-chloro-5′-deoxyribonucleoside derivatives 1 and 3 for hA 1 AR vs hA 3 AR compared to that of the parent 5′-hydroxy compounds CPA and (()-ENBA was rationalized by a molecular modeling analysis. 5′-Chloro-5′-deoxy-(()-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p. D-ribofuranosyl)purine (15), prepared as reported by Hou et al., 7 with (()-endo-norborn-2-yl-amine hydrochloride in the presence of triethylamine in absolute ethanol, followed by sugar deblocking with methanolic ammonia, gave 2-Cl-(()-ENBA (16). Compound 16 was protected as 2′,3′-isopropylidene derivative 17 using camphorsulfonic acid and 2,2-dimethoxypropane in acetone in 80% yield. Conversion of 17 to 5′-chloro derivative 18 was performed by treatment with a mixture of thionyl chloride, pyridine, and acetonitrile. Finally, deprotection of 18 with 70% formic acid at 40°C furnished compound 4. Direct conversion of 2-Cl-(()-ENBA (16) into its 5′-chloro-5′-deoxy derivative 4 using thionyl chloride and pyridine in acetonitrile or thionyl chloride and hexamethylphosphoramide (HMPA) was also tried, but low yields of 4 were obtained.

Research paper thumbnail of Inhibition of HIV-1 replication in macrophages by a heterodinucleotide of lamivudine and tenofovir

Journal of Antimicrobial Chemotherapy, 2007

Objectives: (i) To generate a new heterodinucleotide (3TCpPMPA) comprising the drugs lamivudine a... more Objectives: (i) To generate a new heterodinucleotide (3TCpPMPA) comprising the drugs lamivudine and tenofovir which have been shown to act synergistically and (ii) to protect macrophages from 'de novo' HIV-1-infection through its administration.

Research paper thumbnail of Synthesis and biological activity of novel N6-substituted and 2,N6-disubstituted adenine ribo- and 3′-C-methyl-ribonucleosides as antitumor agents

European Journal of Medicinal Chemistry, 2011

A series of N 6 -aminopurine-9-b-D-ribonucleosides and ribose-modified 3 0 -C-methyl analogues su... more A series of N 6 -aminopurine-9-b-D-ribonucleosides and ribose-modified 3 0 -C-methyl analogues substituted at N 6 -position with a small group like hydroxy, methoxy or amino group or at C2(N 6 ) position have been synthesized and tested against a panel of human leukemia and carcinoma cell lines. N 6 -Hydrazino-9-b-D-ribofuranosyl-purine (5) displayed the best antiproliferative activity in the low micromolar or submicromolar range against all tested tumor cell lines. The activity of this nucleoside is related in part to ribonucleotide reductase inhibition. C2-modification or 3 0 -C-methylation in N 6substituted adenosine analogues leads to a decrease or loss in activity.

Research paper thumbnail of Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors

Bioorganic & Medicinal Chemistry, 2005

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2 0 -MeAD (1) and T-3 0 -MeAD (2) c... more Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2 0 -MeAD (1) and T-3 0 -MeAD (2) containing, respectively, a methyl group at the ribose 2 0 -C-, and 3 0 -C-position of the adenosine moiety, were prepared as potential selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. The synthesis of heterodinucleotides was carried out by CDI-catalyzed coupling reaction of unprotected 2 0 -C-methyl-or 3 0 -C-methyl-adenosine 5 0 -monophosphate with 2 0 ,3 0 -O-isopropylidene-tiazofurin 5 0 -monophosphate, and then deisopropylidenation. Biological evaluation of dinucleotides 1 and 2 as inhibitors of recombinant human IMPDH type I and type II resulted in a good activity. Inhibition of both isoenzymes by T-2 0 -MeAD and T-3 0 -MeAD was noncompetitive with respect to NAD substrate. Binding of T-3 0 -MeAD was comparable to that of parent compound TAD, while T-2 0 -MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2 0 -MeAD and T-3 0 -MeAD were found to inhibit the growth of K562 cells (IC 50 30.7 and 65.0 lM, respectively).

Research paper thumbnail of Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues

Bioorganic & Medicinal Chemistry, 2009

Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria monocytogenes and the ... more Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria monocytogenes and the crystal structure of the enzyme-inhibitor complex has been solved. We have synthesized tiazofurin adenosine disulfide (4) and the disulfide 5, and found that these compounds were moderate inhibitors of human NAD kinase (IC 50 = 110 lM and IC 50 = 87 lM, respectively) and Mycobacterium tuberculosis NAD kinase (IC 50 = 80 lM and IC 50 = 45 lM, respectively). We also found that NAD mimics with a short disulfide (-S-S-) moiety were able to bind in the folded (compact) conformation but not in the common extended conformation, which requires the presence of a longer pyrophosphate (-O-P-O-P-O-) linkage. Since majority of NAD-dependent enzymes bind NAD in the extended conformation, selective inhibition of NAD kinases by disulfide analogues has been observed. Introduction of bromine at the C8 of the adenine ring restricted the adenosine moiety of diadenosine disulfides to the syn conformation making it even more compact. The 8-bromoadenosine adenosine disulfide (14) and its di(8-bromoadenosine) analogue (15) were found to be the most potent inhibitors of human (IC 50 = 6 lM) and mycobacterium NAD kinase (IC 50 = 14-19 lV reported so far. None of the disulfide analogues showed inhibition of lactate-, and inosine monophosphate-dehydrogenase (IMPDH), enzymes that bind NAD in the extended conformation.

Research paper thumbnail of 5′-Carbamoyl derivatives of 2′-C-methyl-purine nucleosides as selective A1 adenosine receptor agonists: Affinity, efficacy, and selectivity for A1 receptor from different species

Bioorganic & Medicinal Chemistry, 2008

A series of 5 0 -carbamoyl and 5 0 -thionocarbamoyl derivatives of 2 0 -C-methyl analogues of the... more A series of 5 0 -carbamoyl and 5 0 -thionocarbamoyl derivatives of 2 0 -C-methyl analogues of the A 1 adenosine receptor (A 1 AR) full agonists N 6 -cyclopentyladenosine (CPA), 2-chloro-N 6 -cyclopentyladenosine (CCPA), N 6 -[3-(R)-tetrahydrofuranyl]adenosine (tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized and evaluated for their affinity for adenosine receptor subtypes from bovine, porcine, and human species. In the N 6 -cyclopentylamino series, the 5 0 -substituted derivatives showed a reduced affinity at the bovine A 1 AR compared to the parent compounds; however, the selectivity for A 1 versus A 2A receptor was retained or increased. The corresponding N 6 -3-(R)-tetrahydrofuranylamino analogues displayed a very low affinity toward the bovine A 1 AR. The 5 0 -methylthionocarbamoyl derivative of 2 0 -Me-CCPA showed the best affinity at porcine A 1 AR with a K i value of 13 nM. At human AR subtypes tecadenoson derivatives showed 2.3-to 5-fold lower affinity at A 1 AR and very low affinity at the other subtypes (A 2A , A 2B , and A 3 ) compared to the corresponding N 6 -cyclopentyl analogues. The 5 0 -carbamoyl and 5 0 -thionocarbamoyl derivatives of 2 0 -Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were found to be partial A 1 agonists at the porcine receptor. Docking studies explained the lower affinity of N 6 -3-(R)-tetrahydrofuranyl-substituted compounds at bovine A 1 AR compared to that of N 6 -cyclopentyl analogues, showing that the oxygen of the tetrahydrofuranyl ring establishes unfavorable electrostatic interactions with the CO oxygen of Asn254. The low binding affinity of the 2 0 -C-methyl-N 6 -3-(R)-tetrahydrofuranyl adenosine analogues at human A 1 AR may be ascribed to the presence of unfavorable interactions between the hydrophilic tetrahydrofuranyl ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274 (TM7).

Research paper thumbnail of Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure

Bioorganic & Medicinal Chemistry, 2010

Small molecules that act on multiple biological targets have been proposed to combat the drug res... more Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed.

Research paper thumbnail of Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

Bioorganic & Medicinal Chemistry, 2008

The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for eva... more The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y 2 , P2Y 4 , and P2Y 6 receptors. The 2-thio modification, found previously to enhance P2Y 2 receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y 2 receptor, in the form of Up 4 -sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, a,b-methylene-UDP, a P2Y 6 receptor agonist; 30, Up 4 -phenyl ester and 34, Up 4 -[1]glucose, selective P2Y 2 receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y 2 receptor agonists; 43, the 2-thio analogue of INS37217 (P 1 -(uridine-5 0 )-P 4 -(2 0 -deoxycytidine-5 0 )tetraphosphate), a potent and selective P2Y 2 receptor agonist.

Research paper thumbnail of Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain

Bioorganic & Medicinal Chemistry, 2011

Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinam... more Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding subsite (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K i = 5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC 50 = 0.45 lM). Compound 4 was as potent as Gleevec (IC 50 = 0.56 lM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K i 's lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N-and A-sub-site of IMPDH.

Research paper thumbnail of Isofuranodiene, a Natural Sesquiterpene Isolated from Wild Celery (Smyrnium olusatrum L.), Protects Rats against Acute Ischemic Stroke

Pharmaceuticals

The myrrh-like furanosesquiterpene isofuranodiene (IFD) is the main constituent of wild celery (S... more The myrrh-like furanosesquiterpene isofuranodiene (IFD) is the main constituent of wild celery (Smyrnium olusatrum L., Apiaceae), an overlooked vegetable that was cultivated during the Roman Empire. In the present study, we investigated the protective effects of IFD pre-treatment against oxidative stress and inflammatory response in an animal model of ischemic stroke. IFD was isolated by the crystallization of Smyrnium olusatrum essential oil, and its structure and purity were confirmed by NMR and HPLC analyses. Acute pre-treatment of IFD (10 mg/kg i.p.) significantly reduced the levels of the inflammatory cytokines IL-1β and TNF-α, the expression of pNF-κB/NF-κB, and the lipid peroxidation indicator MDA. Finally, IFD boosted a faster recovery and better scores in grid-walking and modified neurological severity scores (mNSS) tests. Taken together, these findings indicate IFD as a promising lead compound for the discovery of new treatments of brain ischemia.

Research paper thumbnail of Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure

Small molecules that act on multiple biological targets have been proposed to combat the drug res... more Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed.

Research paper thumbnail of 5'-C-Ethyl-tetrazolyl-N(6)-Substituted Adenosine and 2-Chloro-adenosine Derivatives as Highly Potent Dual Acting A1 Adenosine Receptor Agonists and A3 Adenosine Receptor Antagonists

Journal of medicinal chemistry, Jan 12, 2015

A series of N(6)-substituted-5'-C-(2-ethyl-2H-tetrazol-5-yl)-adenosine and 2-chloro-adenosine... more A series of N(6)-substituted-5'-C-(2-ethyl-2H-tetrazol-5-yl)-adenosine and 2-chloro-adenosine derivatives was synthesized as novel, highly potent dual acting hA1AR agonists and hA3AR antagonists, potentially useful in the treatment of glaucoma and other diseases. The best affinity and selectivity profiles were achieved by N(6)-substitution with a 2-fluoro-4-chloro-phenyl- or a methyl- group. Through an in silico receptor-driven approach, the molecular bases of the hA1- and hA3AR recognition and activation of this series of 5'-C-ethyl-tetrazolyl derivatives were explained.

Research paper thumbnail of Stereoselective Synthesis of Nicotinamide β-Riboside and Nucleoside Analogues

ChemInform, 2004

Stereoselective Synthesis of Nicotinamide β-Riboside and Nucleoside Analogues. -The key elements ... more Stereoselective Synthesis of Nicotinamide β-Riboside and Nucleoside Analogues. -The key elements of the stereoselective synthesis of nicotinamide and nicotinic acid β-ribosides (V) involve the formation of silylated nicotinic bases and their coupling with protected sugars (II) under Vorbruggen's conditions in the presence of a catalytic amount of Tms-O-Tf. This method, carried out under controlled conditions, provide only the β-anomers (IV). Basic hydrolytic deblocking of (IV) at low temperature minimizes cleavage of the glycosidic linkage to afford the desired targets (V) as white solids after purification. -(FRANCHETTI*, P.; PASQUALINI, M.; PETRELLI, R.; RICCIUTELLI, M.; VITA, P.; CAPPELLACCI, L.; Bioorg. Med.

Research paper thumbnail of From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase: Synthesis and biological evaluation of valproic esters of 3′-C-methyladenosine

Bioorganic & Medicinal Chemistry Letters, 2014

We synthesized a series of serum-stable covalently linked drugs derived from 3 0 -C-methyladenosi... more We synthesized a series of serum-stable covalently linked drugs derived from 3 0 -C-methyladenosine (3 0 -Me-Ado) and valproic acid (VPA), which are ribonucleotide reductase (RR) and histone deacetylase (HDAC) inhibitors, respectively. While the combination of free VPA and 3 0 -Me-Ado resulted in a clear synergistic apoptotic effect, the conjugates had lost their HDAC inhibitory effect as well as the corresponding apoptotic activity. Two of the analogs, 2 0 ,5 0 -bis-O-valproyl-3 0 -C-methyladenosine (A160) and 5 0 -O-valproyl-3 0 -C-methyladenosine (A167), showed promising cytotoxic activities against human hematological and solid cancer cell lines. A167 was less potent than A160 but had interesting features as an RR inhibitor. It inhibited RR activity by competing with ATP as an allosteric effector and concomitantly reduced the intracellular deoxyribonucleoside triphosphate (dNTP) pools. A167 represents a novel lead compound, which in contrast to previously used RR nucleoside analogs does not require intracellular kinases for its activity and therefore holds promise against drug resistant tumors with downregulated nucleoside kinases.

Research paper thumbnail of Synthesis, biological evaluation, and molecular modeling of ribose-modified adenosine analogues as adenosine receptor agonists

Journal of Medicinal Chemistry, 2005

A number of 3′-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA... more A number of 3′-C-methyl analogues of selective adenosine receptor agonists such as CPA, CHA, CCPA, 2′-Me-CCPA, NECA, and IB-MECA was synthesized to further investigate the subdomain of the receptor that binds the ribose moiety of the ligands. Affinity data at A 1 , A 2A , and A 3 receptors in bovine brain membranes showed that the 3′-C-modification in adenosine resulted in a decrease of the affinity at all three receptor subtypes. When this modification was combined with N 6 -substitution with groups that induce high potency and selectivity at A 1 receptor, the affinity and selectivity were increased. However, all 3′-C-methyl derivatives proved to be very less active than the corresponding 2′-C-methyl analogues. The most active compound was found to be 3′-Me-CPA which displayed a K i value of 0.35 µM at A 1 receptor and a selectivity for A 1 vs A 2A and A 3 receptors higher than 28-fold. 2′-Me-CCPA was confirmed to be the most selective, high affinity agonist so far known also at human A 1 receptor with a K i value of 3.3 nM and 2903-and 341-fold selective vs human A 2A and A 3 receptors, respectively. In functional assay, 3′-Me-CPA, 3′-Me-CCPA, and 2-Cl-3′-Me-IB-MECA inhibited forskolin-stimulated adenylyl cyclase activity with IC 50 values ranging from 0.3 to 4.9 µM, acting as full agonists. A rhodopsin-based model of the bovine A 1 AR was built to rationalize the higher affinity and selectivity of 2′-C-methyl derivatives of N 6 -substituted-adenosine compared to that of 3′-Cmethyl analogues. In the docking exploration, it was found that 2′-Me-CCPA was able to form a number of interactions with several polar residues in the transmembrane helices TM-3, TM-6, and TM-7 of bA 1 AR which were not preserved in the molecular dynamics simulation of 3′-Me-CCPA/bA 1 AR complex.

Research paper thumbnail of Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice

Experimental Neurology, 2014

Dopamine Adenosine Substantia nigra pars reticulata Levodopa Dyskinesia Mice GABAergic terminals ... more Dopamine Adenosine Substantia nigra pars reticulata Levodopa Dyskinesia Mice GABAergic terminals γ-Aminobutyric acid A receptor (GABA A R)-mediated postsynaptic currents were recorded in brain slices from substantia nigra pars reticulate neurons. The selective adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) in the presence of the dopamine D1 receptor agonist SKF 38393 (SKF) and phosphodiesterase 10A inhibitors (papaverine or AE90074). Under these conditions, DPCPX also increased the amplitude of evoked IPSCs (eIPSCs). The effect of DPCPX was also examined in a mouse model of Parkinson's disease (PD), generated by unilateral denervation of the dopaminergic input to the striatum. In this model, SKF alone was sufficient to increase sIPSCs frequency and eIPSCs amplitude, and these effects were not potentiated by DPCPX. To confirm a depressive effect of A1Rs on the synaptic release of GABA we used the selective A1R agonist 5′-chloro-5′-deoxy-N 6 -(±)-(endo-norborn-2-yl)adenosine (5′Cl5′d-(±)-ENBA) which has limited peripheral actions. We found that 5′Cl5′d-(±)-ENBA decreased sIPSCs frequency, without affecting their amplitude, and decreased eIPSCs amplitude. Importantly, in the PD mouse model, 5′Cl5′d-(±)-ENBA prevented the increase in sIPSC frequency and eIPSC amplitude produced by SKF. Since exaggerated DA transmission along the striato-nigral pathway is involved in the motor complications (e.g. dyskinesia) caused by prolonged and intermittent administration of L-DOPA, we examined the effect of A1R activation in mice with unilateral DA denervation. We found that 5′Cl5′ d-(±)-ENBA, administered in combination with L-DOPA, reduced the development of abnormal involuntary movements. These results indicate the potential benefit of A1R agonists for the treatment of L-DOPA-induced dyskinesia and hyperkinetic disorders providing a mechanistic framework for the study of the interaction between DA and adenosine in the striatonigral system.

Research paper thumbnail of Novel Inhibitors of Inosine Monophosphate Dehydrogenase in Patent Literature of the Last Decade

Recent Patents on Anti-Cancer Drug Discovery, 2013

Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthe... more Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthesis of guanine nucleotides, has received considerable interest in recent years as an important target enzyme, not only for the discovery of anticancer drugs, but also for antiviral, antiparasitic, and immunosuppressive chemotherapy. The field of IMPDH inhibitor research is highly important for providing potential therapeutics against a validated target for disease intervention. This patent review examines the chemical structures and biological activities of recently reported IMPDH inhibitors. Patent databases SciFinder and Espacenet and Delphion were used to locate patent applications that were published between January 2002 and July 2012, claiming chemical structures for use as IMPDH inhibitors. From 2002 to 2012, around 47 primary patent applications have claimed IMPDH inhibitors, which we analyzed by target and applicant. The level of newly published patent applications covering IMPDH inhibitors remains high and a diverse range of scaffolds has been claimed.

Research paper thumbnail of Synthesis and Antitumor Activity of a Heterodinucleotide of BVDU and Gemcitabine

Nucleosides, Nucleotides and Nucleic Acids, 2008

A heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5′,5′-pyrophospate bridg... more A heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5′,5′-pyrophospate bridge (BVDUp2dFdC) has been synthesized and evaluated as antitumor agent against AH13 rat sarcoma cells. BVDUp2dFdC showed a cytotoxicity similar to that of Gemcitabine.

Research paper thumbnail of Antitumor Activity of C -Methyl-β- d -ribofuranosyladenine Nucleoside Ribonucleotide Reductase Inhibitors

Journal of Medicinal Chemistry, 2005

A series of adenosine derivatives substituted at the 1′-, 2′-, or 3′-position of the ribose ring ... more A series of adenosine derivatives substituted at the 1′-, 2′-, or 3′-position of the ribose ring with a methyl group was synthesized and evaluated for antitumor activity. From this study 3′-C-methyladenosine (3′-Me-Ado) emerged as the most active compound, showing activity against human myelogenous leukemia K562, multidrug resistant human leukemia K562IU, human promyelocytic leukemia HL-60, human colon carcinoma HT-29, and human breast carcinoma MCF-7 cell lines with IC 50 values ranging from 11 to 38 µM. Structure-activity relationship studies showed that the structure of 3′-Me-Ado is crucial for the activity. Substitution of a hydrogen atom of the N 6 -amino group with a small alkyl or cycloalkyl group, the introduction of a chlorine atom in the 2-position of the purine ring, or the moving of the methyl group from the 3′-position to other ribose positions brought about a decrease or loss of antitumor activity. The antiproliferative activity of 3′-Me-Ado appears to be related to its ability to deplete both intracellular purine and pyrimidine deoxynucleotides through ribonucleotide reductase inhibition.

Research paper thumbnail of Ribose-Modified Purine Nucleosides as Ribonucleotide Reductase Inhibitors. Synthesis, Antitumor Activity, and Molecular Modeling of N 6 -Substituted 3′- C -Methyladenosine Derivatives

Journal of Medicinal Chemistry, 2008

A series of cycloalkyl, bicycloalkyl, aryl, and heteroaryl N 6 -substituted derivatives of the an... more A series of cycloalkyl, bicycloalkyl, aryl, and heteroaryl N 6 -substituted derivatives of the antitumor agent 3′-C-methyladenosine (3′-Me-Ado), an inhibitor of the R Rnr1 subunit of mammalian ribonucleotide reductase (RR), were synthesized. The cytotoxicity of these compounds was evaluated against a panel of human leukemia and carcinoma cell lines and compared to that of some corresponding N 6 -substituted adenosine analogues. N 6 -cycloalkyl-3′-C-methylribonucleosides 2-7 and N 6 -phenyl analogue 8 were found to inhibit the proliferation of K562 leukemia cells. N 6 -(()-endo-2-norbornyl-3′-C-methyladenosine (7) was found to be the most cytotoxic compound, with GI 50 values slightly higher than that of 3′-Me-Ado against K562 and carcinoma cell lines and 2.7 fold higher cytotoxicity against human promyelocytic leukemia HL-60 cells. The SAR study confirms that an unsubstituted N 6 -amino group is essential for optimal cytotoxicity of 3′-Me-Ado against both K562 and carcinoma cell lines. Computational studies, carried out on the eukaryotic R subunit (Rnr1) of RR from Saccharomyces cereVisiae were performed to rationalize the observed structure-activity relationships.

Research paper thumbnail of N 6 -Cycloalkyl- and N 6 -Bicycloalkyl- C 5′( C 2′)-modified Adenosine Derivatives as High-Affinity and Selective Agonists at the Human A 1 Adenosine Receptor with Antinociceptive Effects in Mice

Journal of Medicinal Chemistry, 2009

To further investigate new potent and selective human A 1 adenosine receptor agonists, we have sy... more To further investigate new potent and selective human A 1 adenosine receptor agonists, we have synthesized a series of 5′-chloro-5′-deoxy-and 5′-(2-fluorophenylthio)-5′-deoxy-N 6 -cycloalkyl(bicycloalkyl)-substituted adenosine and 2′-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A 1 , A 2A , A 2B , and A 3 adenosine receptors. In the series of N 6 -cyclopentyl-and N 6 -(endo-norborn-2-yl)adenosine derivatives, 5′-chloro-5′-deoxy-CPA (1) and 5′-chloro-5′-deoxy-(()-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA 1 vs the other human receptor subtypes. The higher affinity and selectivity of 5′-chloro-5′-deoxyribonucleoside derivatives 1 and 3 for hA 1 AR vs hA 3 AR compared to that of the parent 5′-hydroxy compounds CPA and (()-ENBA was rationalized by a molecular modeling analysis. 5′-Chloro-5′-deoxy-(()-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p. D-ribofuranosyl)purine (15), prepared as reported by Hou et al., 7 with (()-endo-norborn-2-yl-amine hydrochloride in the presence of triethylamine in absolute ethanol, followed by sugar deblocking with methanolic ammonia, gave 2-Cl-(()-ENBA (16). Compound 16 was protected as 2′,3′-isopropylidene derivative 17 using camphorsulfonic acid and 2,2-dimethoxypropane in acetone in 80% yield. Conversion of 17 to 5′-chloro derivative 18 was performed by treatment with a mixture of thionyl chloride, pyridine, and acetonitrile. Finally, deprotection of 18 with 70% formic acid at 40°C furnished compound 4. Direct conversion of 2-Cl-(()-ENBA (16) into its 5′-chloro-5′-deoxy derivative 4 using thionyl chloride and pyridine in acetonitrile or thionyl chloride and hexamethylphosphoramide (HMPA) was also tried, but low yields of 4 were obtained.

Research paper thumbnail of Inhibition of HIV-1 replication in macrophages by a heterodinucleotide of lamivudine and tenofovir

Journal of Antimicrobial Chemotherapy, 2007

Objectives: (i) To generate a new heterodinucleotide (3TCpPMPA) comprising the drugs lamivudine a... more Objectives: (i) To generate a new heterodinucleotide (3TCpPMPA) comprising the drugs lamivudine and tenofovir which have been shown to act synergistically and (ii) to protect macrophages from 'de novo' HIV-1-infection through its administration.

Research paper thumbnail of Synthesis and biological activity of novel N6-substituted and 2,N6-disubstituted adenine ribo- and 3′-C-methyl-ribonucleosides as antitumor agents

European Journal of Medicinal Chemistry, 2011

A series of N 6 -aminopurine-9-b-D-ribonucleosides and ribose-modified 3 0 -C-methyl analogues su... more A series of N 6 -aminopurine-9-b-D-ribonucleosides and ribose-modified 3 0 -C-methyl analogues substituted at N 6 -position with a small group like hydroxy, methoxy or amino group or at C2(N 6 ) position have been synthesized and tested against a panel of human leukemia and carcinoma cell lines. N 6 -Hydrazino-9-b-D-ribofuranosyl-purine (5) displayed the best antiproliferative activity in the low micromolar or submicromolar range against all tested tumor cell lines. The activity of this nucleoside is related in part to ribonucleotide reductase inhibition. C2-modification or 3 0 -C-methylation in N 6substituted adenosine analogues leads to a decrease or loss in activity.

Research paper thumbnail of Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors

Bioorganic & Medicinal Chemistry, 2005

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2 0 -MeAD (1) and T-3 0 -MeAD (2) c... more Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2 0 -MeAD (1) and T-3 0 -MeAD (2) containing, respectively, a methyl group at the ribose 2 0 -C-, and 3 0 -C-position of the adenosine moiety, were prepared as potential selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. The synthesis of heterodinucleotides was carried out by CDI-catalyzed coupling reaction of unprotected 2 0 -C-methyl-or 3 0 -C-methyl-adenosine 5 0 -monophosphate with 2 0 ,3 0 -O-isopropylidene-tiazofurin 5 0 -monophosphate, and then deisopropylidenation. Biological evaluation of dinucleotides 1 and 2 as inhibitors of recombinant human IMPDH type I and type II resulted in a good activity. Inhibition of both isoenzymes by T-2 0 -MeAD and T-3 0 -MeAD was noncompetitive with respect to NAD substrate. Binding of T-3 0 -MeAD was comparable to that of parent compound TAD, while T-2 0 -MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2 0 -MeAD and T-3 0 -MeAD were found to inhibit the growth of K562 cells (IC 50 30.7 and 65.0 lM, respectively).

Research paper thumbnail of Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues

Bioorganic & Medicinal Chemistry, 2009

Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria monocytogenes and the ... more Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria monocytogenes and the crystal structure of the enzyme-inhibitor complex has been solved. We have synthesized tiazofurin adenosine disulfide (4) and the disulfide 5, and found that these compounds were moderate inhibitors of human NAD kinase (IC 50 = 110 lM and IC 50 = 87 lM, respectively) and Mycobacterium tuberculosis NAD kinase (IC 50 = 80 lM and IC 50 = 45 lM, respectively). We also found that NAD mimics with a short disulfide (-S-S-) moiety were able to bind in the folded (compact) conformation but not in the common extended conformation, which requires the presence of a longer pyrophosphate (-O-P-O-P-O-) linkage. Since majority of NAD-dependent enzymes bind NAD in the extended conformation, selective inhibition of NAD kinases by disulfide analogues has been observed. Introduction of bromine at the C8 of the adenine ring restricted the adenosine moiety of diadenosine disulfides to the syn conformation making it even more compact. The 8-bromoadenosine adenosine disulfide (14) and its di(8-bromoadenosine) analogue (15) were found to be the most potent inhibitors of human (IC 50 = 6 lM) and mycobacterium NAD kinase (IC 50 = 14-19 lV reported so far. None of the disulfide analogues showed inhibition of lactate-, and inosine monophosphate-dehydrogenase (IMPDH), enzymes that bind NAD in the extended conformation.

Research paper thumbnail of 5′-Carbamoyl derivatives of 2′-C-methyl-purine nucleosides as selective A1 adenosine receptor agonists: Affinity, efficacy, and selectivity for A1 receptor from different species

Bioorganic & Medicinal Chemistry, 2008

A series of 5 0 -carbamoyl and 5 0 -thionocarbamoyl derivatives of 2 0 -C-methyl analogues of the... more A series of 5 0 -carbamoyl and 5 0 -thionocarbamoyl derivatives of 2 0 -C-methyl analogues of the A 1 adenosine receptor (A 1 AR) full agonists N 6 -cyclopentyladenosine (CPA), 2-chloro-N 6 -cyclopentyladenosine (CCPA), N 6 -[3-(R)-tetrahydrofuranyl]adenosine (tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized and evaluated for their affinity for adenosine receptor subtypes from bovine, porcine, and human species. In the N 6 -cyclopentylamino series, the 5 0 -substituted derivatives showed a reduced affinity at the bovine A 1 AR compared to the parent compounds; however, the selectivity for A 1 versus A 2A receptor was retained or increased. The corresponding N 6 -3-(R)-tetrahydrofuranylamino analogues displayed a very low affinity toward the bovine A 1 AR. The 5 0 -methylthionocarbamoyl derivative of 2 0 -Me-CCPA showed the best affinity at porcine A 1 AR with a K i value of 13 nM. At human AR subtypes tecadenoson derivatives showed 2.3-to 5-fold lower affinity at A 1 AR and very low affinity at the other subtypes (A 2A , A 2B , and A 3 ) compared to the corresponding N 6 -cyclopentyl analogues. The 5 0 -carbamoyl and 5 0 -thionocarbamoyl derivatives of 2 0 -Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were found to be partial A 1 agonists at the porcine receptor. Docking studies explained the lower affinity of N 6 -3-(R)-tetrahydrofuranyl-substituted compounds at bovine A 1 AR compared to that of N 6 -cyclopentyl analogues, showing that the oxygen of the tetrahydrofuranyl ring establishes unfavorable electrostatic interactions with the CO oxygen of Asn254. The low binding affinity of the 2 0 -C-methyl-N 6 -3-(R)-tetrahydrofuranyl adenosine analogues at human A 1 AR may be ascribed to the presence of unfavorable interactions between the hydrophilic tetrahydrofuranyl ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274 (TM7).

Research paper thumbnail of Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure

Bioorganic & Medicinal Chemistry, 2010

Small molecules that act on multiple biological targets have been proposed to combat the drug res... more Small molecules that act on multiple biological targets have been proposed to combat the drug resistance commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized, and evaluated in biological assays. Key features, including the linker length, linker functionality, substitution position, and interacting groups, have been explored. Their individual contribution to the inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed.

Research paper thumbnail of Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

Bioorganic & Medicinal Chemistry, 2008

The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for eva... more The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y 2 , P2Y 4 , and P2Y 6 receptors. The 2-thio modification, found previously to enhance P2Y 2 receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y 2 receptor, in the form of Up 4 -sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, a,b-methylene-UDP, a P2Y 6 receptor agonist; 30, Up 4 -phenyl ester and 34, Up 4 -[1]glucose, selective P2Y 2 receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y 2 receptor agonists; 43, the 2-thio analogue of INS37217 (P 1 -(uridine-5 0 )-P 4 -(2 0 -deoxycytidine-5 0 )tetraphosphate), a potent and selective P2Y 2 receptor agonist.

Research paper thumbnail of Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain

Bioorganic & Medicinal Chemistry, 2011

Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinam... more Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding subsite (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K i = 5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC 50 = 0.45 lM). Compound 4 was as potent as Gleevec (IC 50 = 0.56 lM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K i 's lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N-and A-sub-site of IMPDH.