A novel achiral seco-cyclopropylpyrido[e]indolone (CPyI) analog of CC-1065 and the duocarmycins: Synthesis, DNA interactions, in vivo anticancer and anti-parasitic evaluation (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2010
The design, synthesis and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo [2,3e]indol-4-one-6-carboxylate (COI) derivatives are detailed representing analogs of duocarmycin SA containing an oxazole replacement for the fused pyrrole found in the alkylation subunit.
Synthesis and evaluation of a thio analogue of duocarmycin SA
Bioorganic & Medicinal Chemistry Letters, 2009
The design, synthesis, and preliminary evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]thieno [3,2e]indol-4-one-6-carboxylate (CTI) derivatives are detailed representing a single atom change (N to S) embedded in the duocarmycin SA alkylation subunit.
Toxins, 2009
The natural antibiotics CC‑1065 and the duocarmycins are highly cytotoxic compounds which however are not suitable for cancer therapy due to their general toxicity. We have developed glycosidic prodrugs of seco-analogues of these antibiotics for a selective cancer therapy using conjugates of glycohydrolases and tumour-selective monoclonal antibodies for the liberation of the drugs from the prodrugs predominantly at the tumour site. For the determination of structure activity relationships of the different seco-drugs, experiments addressing their interaction with synthetic DNA were performed. Using electro-spray mass spectrometry and high performance liquid chromatography, the experiments revealed a correlation of the stability of these drugs with their cytotoxicity in cell culture investigations. Furthermore, it was shown that the drugs bind to AT-rich regions of double-stranded DNA and the more cytotoxic drugs induce DNA fragmentation at room temperature in several of the selected ...
Hybrid molecules based on distamycin A as potential antitumor agents
Arkivoc, 2005
Many natural and synthetic anticancer agents with the ability to interact with DNA have been discovered, but most of them have relatively low therapeutic index. This is probably related to the fact that these derivatives cause DNA damage in an unspecific manner, inducing unselective growth inhibition and death, both in neoplastic and in highly proliferative normal tissues. For these reasons, there has been considerable interest in finding small molecules able to alkylate the DNA with a much higher degree of sequence specificity and to modify the function of nucleic acids irreversibly. Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently under investigation. Distamycin A has driven researcher's attention not only for the biological activity, but also for its non intercalative binding to the minor groove of doublestranded B-DNA, where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The pyrrole-amide skeleton of distamycin A has also been used as DNA sequence selective vehicle for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of distamycin itself. The DNA alkylating and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame.
Journal of Medicinal Chemistry, 2001
We have synthesized and evaluated a series of hybrids, denoted 22-27, for in vitro cytotoxic activity against a variety of cancer cell lines. These hybrids represent a molecular combination of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A and two pyrazole analogues of the left-hand segment called cyclopropylpyrroloindole (CPI) of the potent antitumor antibiotic (+)-CC-1065. These novel water-soluble hybrids have been designed to enhance the minor groove binding ability of alkylating units 20 and 21, which should increase their clinical appeal by overcoming the administration problems of (+)-CC-1065 derivatives. The DNA alkylating and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that, in general, and especially for 22-24, the cytotoxicity of the hybrids was much greater than that of the alkylating units alone. In only one case, compound 27, did the hybrid have cytotoxic activity comparable to that of the alkylating unit alone against FM3A/0 cells. The broadest spectrum of activity and greatest potency was shown by the hybrid 24, in which the alkylating unit 20 and the deformyl distamycin A are tethered by 1-methyl 2,5-dicarbonyl pyrazole, with IC 50 values for the different tumor cell lines ranging from 7 to 71 nM. For compounds 22-24, the increase of the length of the pseudopeptidic moiety from one to three N-methylpyrrole residues led to an increased cytotoxicity. Among the hybrids tested for their inhibitory effects on the proliferation of murine L1210 leukemia cell line, compound 24 proved to be the most active (IC 50 ) 7.4 nM), and in the sequencing gel experiments, it showed the strongest and most highly sequence-specific DNA alkylation activity. For compounds 22-24, the sequence specificity of DNA alkylation appears to be affected by the modification of the number of pyrrole rings, and the correlation between cytotoxicity and alkylation pattern suggests that 24 exerts its cytotoxicity through DNA sequence-specific alkylation of the third adenine located in the sequence 5′-ACAAAAATCG-3′. The two other hybrids 22 and 23 were slightly less active for tumor cell proliferation, with IC 50 values of 58 and 19 nM, respectively. With only one exception, none of the compounds was endowed with antiviral activity at subtoxic concentrations. Compound 24 inhibited the effect of vaccinia virus at a concentration that was significantly lower than its minimum cytotoxic concentration for the E 6 SM host cells. These compounds gave distinct patterns of alkylation in AT-rich sequences, indicating that minor structural changes produced marked alterations in sequence selectivity.
Synthesis and antitumor activity of a new class of water soluble camptothecin derivatives
Bioorganic & Medicinal Chemistry Letters, 1996
Key words: anthramycin, pyraz0lo~4.3-elpyrrolo[l~-al[l.4]diazep analogs, antitumor activity. synthesis. Abshoct: A new class of Pyrrolo[l~4lbenzodiazpines (PBDs) analogs featuring apyrazolo[4,3-e]pyrrolo[l~~)[l.4]~~ ring system has been designed and synthesizexl. In these compounds the A-benzene ring, character&tic of PBDs, has been replaced by a dimethylpyrazole ring, a modification suggested by mcdelling studies performed on the PBD base structure. Biological evaluation revealed appreciable antitumor activity for compounds 14 and 15 (8.84-22.4 PM) which encourages further investigation of the e or N7 alkyl pyrazole analogs. Pyrrolo[ 1,4]benzodiazepines (PBDs) are potent antitumor antibiotics derived from various Streptomyces species showing interesting properties from both synthetic and biological standpoir&. Natural products belonging to this family include Anthramycin. Tomaymycin, Neothramycins A and B, Sibiromycin and Chicamycin. The antitumor activity of these natural products is believed to involve the formation of a labile covalent aminal linkage between the carbinolamine carbon (Cl 1) of the antibiotics and the 2-amino group of guanine residues within the minor groove of DNA2. Reaction with guanines in specific sequences results in DNA sequence specificity. The resulting DNA-antibiotic adduct inhibits DNA replication.
British Journal of Cancer, 1999
PNU 151807 is a new synthetic α-bromoacryloyl derivative of distamycin A. In the present study we investigated the DNA interaction and the mechanism of action of this compound in parallel with the distamycin alkylating derivative, tallimustine. PNU 151807 possesses a good cytotoxic activity in in vitro growing cancer cells, even superior to that found for tallimustine. By footprinting experiments we found that PNU 151807 and tallimustine interact non-covalently with the same AT-rich DNA regions. However, differently from tallimustine, PNU 151807 failed to produce any DNA alkylation as assessed by Taq stop assay and N3 or N7-adenine alkylation assay in different DNA sequences. PNU 151807, like tallimustine, is able to induce an activation of p53, and consequently of p21 and BAX in a human ovarian cancer cell line (A2780) expressing wild-type p53. However, disruption of p53 function by HPV16-E6 does not significantly modify the cytotoxic activity of the compound. Flow cytometric analysis of cells treated with equitoxic concentrations of PNU 151807 and tallimustine showed a similar induction of accumulation of cells in the G2 phase of the cell cycle but with a different time course. When tested against recombinant proteins, only the compound PNU 151807 (and not tallimustine or distamycin A) is able to abolish the in vitro kinase activity of CDK2-cyclin A, CDK2-cyclin E and cdc2-cyclin B complexes. The results obtained showed that PNU 151807 seems to have a mechanism of action completely different from that of its parent compound tallimustine, possibly involving the inhibition of cyclin-dependent kinases activity, and clearly indicate PNU 151807 as a new non-covalent minor groove binder with cytotoxic activity against cancer cells.
Biological Evaluation of an Antibiotic DC‐81–Indole Conjugate Agent in Human Melanoma Cell Lines
The Kaohsiung Journal of Medical Sciences, 2003
Pyrrolo[2, 1-c][1, 4]benzodiazepines (PBDs) are potent inhibitors of nucleic acid synthesis because of their ability to recognize and bind to specific sequences of DNA and form a labile covalent adduct. DC-81, an antitumor antibiotic produced by Streptomyces species, is a PBD. We combined DC-81 and an indole carboxylate moiety to synthesize a hybrid designed to have much higher sequence selectivity in DNA interactivity. In this paper, the cytotoxic potency of the hybrid in human melanoma cell lines was studied. XTT assay demonstrated that the DC-81-indole conjugate possessed cytotoxicity against human melanoma cell lines.