Linda Tomašković - Academia.edu (original) (raw)
Papers by Linda Tomašković
Progress in Medicinal Chemistry, 2018
This chapter will discuss the recent literature of macrocycles and drug-like property space movin... more This chapter will discuss the recent literature of macrocycles and drug-like property space moving beyond the rule of five (bRo5). Trends in chemical classes that fall within this definition are discussed and the impact of the latest technologies in the field assessed. The physicochemical properties, which have provided both successes and challenges, especially in scale-up, are discussed. A recent patent literature is reviewed and the chapter concludes with a perspective on the future of macrocyclic drug discovery.
HeI photoelectron (PE) spectra of 1,11-dimethyl-5,7-dihydro-dibenzo[c,e]oxepine (1), 1,11-dimethy... more HeI photoelectron (PE) spectra of 1,11-dimethyl-5,7-dihydro-dibenzo[c,e]oxepine (1), 1,11-dimethyl-5,7-dihydro-dibenzo[c,e]thiepine (2), 1,11-dimethyl-5,7-dihydro-dibenzo[c,e]thiepine-S-oxide (3), 1,6,11-trimethyl-6,7-dihydro-5H-dibenzo[c,e]azepine (4), and 5,11-dimethyl-4,5,6,10,11,12-hexahydro-5,11-diaza-dibenzo[ef,kl]heptalene (5) have been measured. The low energy region of the spectra has been analyzed using semiempirical PM3, AM1 and MNDO SCF MO calculations (assuming the validity of Koopmans' theorem (Physica 1 (1934) 104) as well as empirical arguments (Franck-Condon (FC) envelopes) and correlation with PE spectra of similar molecules. Their electronic structure might be responsible for their chemical properties.
In addition to antibacterial activity, some macrolide antibiotics, such as azithromycin and clari... more In addition to antibacterial activity, some macrolide antibiotics, such as azithromycin and clarithromycin, also exhibit anti-inflammatory properties in vitro and in vivo, although the targets and mechanism(s) of action remain unknown. The aim of the present study was to identify protein targets of azithromycin and clarithromycin which could potentially explain their anti-inflammatory effects. Using chemical proteomics approach, based on compound-immobilized affinity chromatography, valosin containing protein (VCP) was identified as a potential target of the macrolides. Validation studies confirmed the interaction of macrolides and VCP and gave some structural characteristics of this interaction. Cell based assays however, including the use of gene silencing and the study of VCP specific cellular functions in J774.A1 (murine macrophage) and IB3-1 (human cystic fibrotic epithelial) cell lines, failed to confirm an association between the binding of the macrolides to VCP and anti-infl...
In the title compound, C 17 H 19 N, the central seven-membered azepine ring adopts a twisted-boat... more In the title compound, C 17 H 19 N, the central seven-membered azepine ring adopts a twisted-boat conformation. The molecule exhibits a huge deviation from planarity by rotation of the two fused ortho-methyl-substituted phenyl rings around the central C12-C14 single bond. The dihedral angle between the planes of these two rings amounts to 56.05(4)°, with a cisoid arrangement around the C12-C14 bond. Because of this non-planarity, the molecule is axially chiral.
Progress in Medicinal Chemistry
Current topics in medicinal chemistry, Sep 27, 2016
Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are com... more Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encour...
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17b-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Structural Chemistry, 2009
Nitration of a-resorcylic acid (3,5-dihydroxybenzoic acid) to 3,5-dihydroxy-2-nitrobenzoic acid (... more Nitration of a-resorcylic acid (3,5-dihydroxybenzoic acid) to 3,5-dihydroxy-2-nitrobenzoic acid (1) and 3,5-dihydroxy-4-nitrobenzoic acid (2), their separation, and crystallization is described. Crystal structures of 1, 1 Á 3H 2 O, and 2 were determined by X-ray single-crystal diffraction analysis and compared with DFT-calculated structures. An intramolecular hydrogen bond between the nitro group and o-hydroxyl group(s) occurs in all investigated structures. Intermolecular hydrogen bonds and pÁÁÁp stacking interactions determine the molecular packing. Additionally, NÁÁÁO interactions have a crucial role in arrangement of the molecules in the crystal structures of 1 and 2. DFT calculations in the gas phase and in the solution reveal that minor product 2 is a more stable regioisomer than 1, the major product in the nitration reaction.
Bioorganic Medicinal Chemistry, 2013
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17β-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Acta Crystallographica Section C Crystal Structure Communications, May 29, 2013
![Research paper thumbnail of (�)-6,7-Dihydro-1,6,11-trimethyl-5 H -dibenz[ c , e ]azepine](https://attachments.academia-assets.com/74975791/thumbnails/1.jpg)
](Acta Crystallogr C Cryst Str, 1998
Bioorganic & Medicinal Chemistry
The novel racemic indolinospirobenzopyrans (5-7), indolinospironaphthopyrans (11-14) and indolino... more The novel racemic indolinospirobenzopyrans (5-7), indolinospironaphthopyrans (11-14) and indolinospironaphtho-1,4-oxazine (17) were synthesized by an aldol type of condensation of 1',3',3'-trimethyl-2 '-methyleneindoline and its 5-substituted derivatives with an appropriately substituted hydroxybenzaldehyde, hydroxynaphthaldehyde or nitrosonaphthol. An unequivocal proof of the stereostructures of 9 and 17 was obtained by the single-crystal X-ray diffraction method. A substituted indoline ring and the benzopyran ring in 9 and the naphtho-1,4-oxazine moiety in 17 are interconnected via the common chiral atom and positioned almost perpendicularly to each other. The five-membered 2,3-dihydropyrrolo moiety of the indoline ring adopts an envelope conformation in both structures. Of all the compounds of this series, spirobipyridopyran (1) inhibited specifically the growth of human melanoma (HBL) (IC(50): 0.9 microM) cells but not the growth of normal fibroblasts (WI38). Indolinospirobenzopyrans (8-10) showed significant cytostatic activities against all tumor cell lines. However, these compounds also exhibited a cytotoxic effect on normal human fibroblasts. The indolinospirobenzopyrans 4, 6-8, 10 and the indolinospironaphtho-1,4-oxazine 16 showed, albeit modest, selectivity as antiviral agents against varicella-zoster virus (VZV) and/or cytomegalovirus (CMV) (EC(50) within the concentration range of 1.0-12.6 microM).
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17b-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Acta Crystallographica Section C Crystal Structure Communications
Enantiomer A Journal of Stereochemistry
![Research paper thumbnail of (±)-6,7-Dihydro-1,6,11-trimethyl-5 H -dibenz[ c , e ]azepine](https://attachments.academia-assets.com/74975790/thumbnails/1.jpg)
](Acta Crystallographica Section C Crystal Structure Communications, 1998
ABSTRACT Chiral spirobinaphtopyrans 1–9 were synthesised using the acid catalyzed aldol condensat... more ABSTRACT Chiral spirobinaphtopyrans 1–9 were synthesised using the acid catalyzed aldol condensation of 2-hydroxy-1-naphthaldehyde or 1-hydroxy-2-naphthaldehyde with the appropriate ketone and subsequent reaction of the isolated pyrylium salt with base. Separation or enrichment of enantiomers was accomplished by low-pressure liquid chromatography (LPLC) on triacetylcellulose, tribenzoylcellulose, or (+)-poly(triphenyl- methyl methacrylate) on SiO2. The barriers to thermal racemization were determined by dynamic 1H NMR measurements and by on-line or off-line measurements of the enriched enantiomers after LPLC. Barriers to thermal racemization for reversible cleavage of the Cspiro–O bond in 1–9 were found to be in the range 85–105 kJ/mol and are rationalized by steric and electronic effects. The ΔG≠ values decrease with decreasing length of the bridge or decreasing size of substituents in the 3 and 3′ positions. Therefore, ΔG≠ for 7>9>6, 3>2, and 4>1. Geometrical data from X-ray crystal structure analysis show that the mean value of the Cspiro–O bond length in the spirobibenzopyran 14 is shorter, i.e., the bond is stronger than that in the spirobinaphtho derivatives 4, 3, and 6. This bond-length shortening is explained by the weaker conjugation of the oxygen π-lone electron pair with the π-system of the benzene ring in 14 compared to the naphthalene moiety in 3, 4, and 6. Chirality 11:363–372, 1999. © 1999 Wiley-Liss, Inc.
Organometallics, 2000
Since the discovery of [60]fullerene 1 and its synthesis in large-scale amounts, 2 the organometa... more Since the discovery of [60]fullerene 1 and its synthesis in large-scale amounts, 2 the organometallic chemistry of C 60 , primarily including the synthesis, structural characterization, and properties of transition-metal [60]fullerene complexes, has attracted great attention. 3 From the ...
Progress in Medicinal Chemistry, 2018
This chapter will discuss the recent literature of macrocycles and drug-like property space movin... more This chapter will discuss the recent literature of macrocycles and drug-like property space moving beyond the rule of five (bRo5). Trends in chemical classes that fall within this definition are discussed and the impact of the latest technologies in the field assessed. The physicochemical properties, which have provided both successes and challenges, especially in scale-up, are discussed. A recent patent literature is reviewed and the chapter concludes with a perspective on the future of macrocyclic drug discovery.
HeI photoelectron (PE) spectra of 1,11-dimethyl-5,7-dihydro-dibenzo[c,e]oxepine (1), 1,11-dimethy... more HeI photoelectron (PE) spectra of 1,11-dimethyl-5,7-dihydro-dibenzo[c,e]oxepine (1), 1,11-dimethyl-5,7-dihydro-dibenzo[c,e]thiepine (2), 1,11-dimethyl-5,7-dihydro-dibenzo[c,e]thiepine-S-oxide (3), 1,6,11-trimethyl-6,7-dihydro-5H-dibenzo[c,e]azepine (4), and 5,11-dimethyl-4,5,6,10,11,12-hexahydro-5,11-diaza-dibenzo[ef,kl]heptalene (5) have been measured. The low energy region of the spectra has been analyzed using semiempirical PM3, AM1 and MNDO SCF MO calculations (assuming the validity of Koopmans' theorem (Physica 1 (1934) 104) as well as empirical arguments (Franck-Condon (FC) envelopes) and correlation with PE spectra of similar molecules. Their electronic structure might be responsible for their chemical properties.
In addition to antibacterial activity, some macrolide antibiotics, such as azithromycin and clari... more In addition to antibacterial activity, some macrolide antibiotics, such as azithromycin and clarithromycin, also exhibit anti-inflammatory properties in vitro and in vivo, although the targets and mechanism(s) of action remain unknown. The aim of the present study was to identify protein targets of azithromycin and clarithromycin which could potentially explain their anti-inflammatory effects. Using chemical proteomics approach, based on compound-immobilized affinity chromatography, valosin containing protein (VCP) was identified as a potential target of the macrolides. Validation studies confirmed the interaction of macrolides and VCP and gave some structural characteristics of this interaction. Cell based assays however, including the use of gene silencing and the study of VCP specific cellular functions in J774.A1 (murine macrophage) and IB3-1 (human cystic fibrotic epithelial) cell lines, failed to confirm an association between the binding of the macrolides to VCP and anti-infl...
In the title compound, C 17 H 19 N, the central seven-membered azepine ring adopts a twisted-boat... more In the title compound, C 17 H 19 N, the central seven-membered azepine ring adopts a twisted-boat conformation. The molecule exhibits a huge deviation from planarity by rotation of the two fused ortho-methyl-substituted phenyl rings around the central C12-C14 single bond. The dihedral angle between the planes of these two rings amounts to 56.05(4)°, with a cisoid arrangement around the C12-C14 bond. Because of this non-planarity, the molecule is axially chiral.
Progress in Medicinal Chemistry
Current topics in medicinal chemistry, Sep 27, 2016
Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are com... more Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encour...
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17b-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Structural Chemistry, 2009
Nitration of a-resorcylic acid (3,5-dihydroxybenzoic acid) to 3,5-dihydroxy-2-nitrobenzoic acid (... more Nitration of a-resorcylic acid (3,5-dihydroxybenzoic acid) to 3,5-dihydroxy-2-nitrobenzoic acid (1) and 3,5-dihydroxy-4-nitrobenzoic acid (2), their separation, and crystallization is described. Crystal structures of 1, 1 Á 3H 2 O, and 2 were determined by X-ray single-crystal diffraction analysis and compared with DFT-calculated structures. An intramolecular hydrogen bond between the nitro group and o-hydroxyl group(s) occurs in all investigated structures. Intermolecular hydrogen bonds and pÁÁÁp stacking interactions determine the molecular packing. Additionally, NÁÁÁO interactions have a crucial role in arrangement of the molecules in the crystal structures of 1 and 2. DFT calculations in the gas phase and in the solution reveal that minor product 2 is a more stable regioisomer than 1, the major product in the nitration reaction.
Bioorganic Medicinal Chemistry, 2013
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17β-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Acta Crystallographica Section C Crystal Structure Communications, May 29, 2013
Acta Crystallogr C Cryst Str, 1998
Bioorganic & Medicinal Chemistry
The novel racemic indolinospirobenzopyrans (5-7), indolinospironaphthopyrans (11-14) and indolino... more The novel racemic indolinospirobenzopyrans (5-7), indolinospironaphthopyrans (11-14) and indolinospironaphtho-1,4-oxazine (17) were synthesized by an aldol type of condensation of 1',3',3'-trimethyl-2 '-methyleneindoline and its 5-substituted derivatives with an appropriately substituted hydroxybenzaldehyde, hydroxynaphthaldehyde or nitrosonaphthol. An unequivocal proof of the stereostructures of 9 and 17 was obtained by the single-crystal X-ray diffraction method. A substituted indoline ring and the benzopyran ring in 9 and the naphtho-1,4-oxazine moiety in 17 are interconnected via the common chiral atom and positioned almost perpendicularly to each other. The five-membered 2,3-dihydropyrrolo moiety of the indoline ring adopts an envelope conformation in both structures. Of all the compounds of this series, spirobipyridopyran (1) inhibited specifically the growth of human melanoma (HBL) (IC(50): 0.9 microM) cells but not the growth of normal fibroblasts (WI38). Indolinospirobenzopyrans (8-10) showed significant cytostatic activities against all tumor cell lines. However, these compounds also exhibited a cytotoxic effect on normal human fibroblasts. The indolinospirobenzopyrans 4, 6-8, 10 and the indolinospironaphtho-1,4-oxazine 16 showed, albeit modest, selectivity as antiviral agents against varicella-zoster virus (VZV) and/or cytomegalovirus (CMV) (EC(50) within the concentration range of 1.0-12.6 microM).
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17b-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Acta Crystallographica Section C Crystal Structure Communications
Enantiomer A Journal of Stereochemistry
Acta Crystallographica Section C Crystal Structure Communications, 1998
ABSTRACT Chiral spirobinaphtopyrans 1–9 were synthesised using the acid catalyzed aldol condensat... more ABSTRACT Chiral spirobinaphtopyrans 1–9 were synthesised using the acid catalyzed aldol condensation of 2-hydroxy-1-naphthaldehyde or 1-hydroxy-2-naphthaldehyde with the appropriate ketone and subsequent reaction of the isolated pyrylium salt with base. Separation or enrichment of enantiomers was accomplished by low-pressure liquid chromatography (LPLC) on triacetylcellulose, tribenzoylcellulose, or (+)-poly(triphenyl- methyl methacrylate) on SiO2. The barriers to thermal racemization were determined by dynamic 1H NMR measurements and by on-line or off-line measurements of the enriched enantiomers after LPLC. Barriers to thermal racemization for reversible cleavage of the Cspiro–O bond in 1–9 were found to be in the range 85–105 kJ/mol and are rationalized by steric and electronic effects. The ΔG≠ values decrease with decreasing length of the bridge or decreasing size of substituents in the 3 and 3′ positions. Therefore, ΔG≠ for 7>9>6, 3>2, and 4>1. Geometrical data from X-ray crystal structure analysis show that the mean value of the Cspiro–O bond length in the spirobibenzopyran 14 is shorter, i.e., the bond is stronger than that in the spirobinaphtho derivatives 4, 3, and 6. This bond-length shortening is explained by the weaker conjugation of the oxygen π-lone electron pair with the π-system of the benzene ring in 14 compared to the naphthalene moiety in 3, 4, and 6. Chirality 11:363–372, 1999. © 1999 Wiley-Liss, Inc.
Organometallics, 2000
Since the discovery of [60]fullerene 1 and its synthesis in large-scale amounts, 2 the organometa... more Since the discovery of [60]fullerene 1 and its synthesis in large-scale amounts, 2 the organometallic chemistry of C 60 , primarily including the synthesis, structural characterization, and properties of transition-metal [60]fullerene complexes, has attracted great attention. 3 From the ...