Synthesis and Biological Evaluation of Novel Resveratrol and Combretastatin A4 Derivatives as Potent Anti-Cancer Agents

Resveratrol has been reported as a potential anticancer agent but cannot be used as an antitumor drug due to its chemical and metabolic instability. We have designed and synthesized 184 novel compounds related to resveratrol in an attempt to produce more potent and drug-like molecules. We have identified a tetrazole analog of resveratrol, ST-145(a) as a lead anticancer agent from the resveratrol analog series of compounds with a GI50 value of less than 10nM against almost all the human cancer cell lines in the National Cancer Institute’s screening panel. In a separate study, we tested the hypothesis that the limited bioavailability of resveratrol, can be improved by synthesizing analogs which would be glucuronidated at a lower rate than resveratrol itself. We demonstrated that ST-05 and ST-12(a) exhibit lower glucuronidation profiles when compared to resveratrol and that these synthesized stilbenoids likely represent useful scaffolds for the design of efficacious resveratrol analogs. We have also initiated a new discovery program to identify selective CB1 and CB2 receptor ligands from a library of novel stilbene scaffolds structurally related to the resveratrol molecule. From the screened resveratrol analogs, two compounds were identified as selective CB2 and CB1 ligands. Compound ST-179 had 47-fold selectivity for CB2 (Ki = 284 nM) compared to CB1, while compound ST-160 was 2-fold selective for CB1 (Ki = 400 nM) compared to the CB2 receptor. These structural analogs have the potential for development as novel cannabinoid therapeutics for treatment of obesity and/or drug dependency. Combretastatin A4 (CA-4) is one of the most potent antiangiogenic and antimitotic agents of natural origin. However, CA-4 suffers from chemical instability due to cis-trans isomerism in solution. To circumvent this problem, we have developed a facile procedure for the synthesis of novel 4,5-diaryl-2H-1,2,3-triazoles as CA-4 analogs to constrain the molecule to its cis-configuration. Twenty three triazoles were prepared as CA-4 analogs and submitted for anticancer screening. Among these CA-4 analogs, ST-467 and ST-145(b) can be considered as lead anticancer agents from this series, and further investigation against various cancer cell types in vivo with this class of compound may provide novel therapeutic avenues for treatment

Comparison of Crystal Structures of 4-(benzo[\u3cem\u3eb\u3c/em\u3e]thiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)-2\u3cem\u3eH\u3c/em\u3e-1,2,3-triazole and 4-(benzo[\u3cem\u3eb\u3c/em\u3e]thiophen-2-yl)-2-methyl-5-(3,4,5-trimethoxyphenyl)-2\u3cem\u3eH\u3c/em\u3e-1,2,3-triazole

The title compound, C19H17N3O3S (I), was prepared by a [3 + 2]cyclo­addition azide condensation reaction using sodium azide and l-proline as a Lewis base catalyst. N-Methyl­ation of compound (I) using CH3I gave compound (II), C20H19N3O3S. The benzo­thio­phene ring systems in (I) and (II) are almost planar, with r.m.s deviations from the mean plane = 0.0205 (14) in (I) and 0.016 (2) Å in (II). In (I) and (II), the triazole rings make dihedral angles of 32.68 (5) and 10.43 (8)°, respectively, with the mean planes of the benzo­thio­phene ring systems. The trimeth­oxy phenyl rings make dihedral angles with the benzo­thio­phene rings of 38.48 (4) in (I) and 60.43 (5)° in (II). In the crystal of (I), the mol­ecules are linked into chains by N—H⋯O hydrogen bonds with R 2 1(5) ring motifs. After the N-methyl­ation of structure (I), no hydrogen-bonding inter­actions were observed for structure (II). The crystal structure of (II) has a minor component of disorder that corresponds to a 180° flip of the benzo­thio­phene ring system [occupancy ratio 0.9363 (14):0.0637 (14)]

Crystal Structure of 4,5-bis-(3,4,5-trimethoxyphenyl)-2\u3cem\u3eH\u3c/em\u3e-1,2,3-triazole methanol monosolvate

The title compound, C20H23N3O6·CH3OH, was synthesized by [3 + 2] cyclo­addition of (Z)-2,3-bis­(3,4,5-tri­meth­oxy­phen­yl)acrylo­nitrile with sodium azide and ammonium chloride in DMF/water. The central nitro­gen of the triazole ring is protonated. The dihedral angles between the triazole ring and the 3,4,5-tri­meth­oxy­phenyl ring planes are 34.31 (4) and 45.03 (5)°, while that between the 3,4,5-tri­meth­oxy­phenyl rings is 51.87 (5)°. In the crystal, the mol­ecules, along with two methanol solvent mol­ecules are linked into an R 4 4(10) centrosymmetric dimer by N—H⋯O and O—H⋯N hydrogen bonds

(Z)-2-{2,4-Dimethoxy-6-[(E)-4-methoxystyryl]benzylidene}quinuclidin-3-one

The crystal structure of the title compound, C25H27NO4, shows the presence of a double bond with Z geometry which connects the quinuclidin-3-one ring and the trimethoxyresveratrol moiety. The dihedral angle between the two benzene rings in the stilbene skeleton is 32.80 (8)°

Monosuccinate ester of melampomagnolide B

The title monosuccinate derivative of melampomagnolide B [systematic name: 4-(((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methoxy)-4-oxobutanoic acid], C19H24O7, was obtained from the reaction of melampomagnolide B with succinic anhydride under nucleophilic addition reaction conditions. The molecule is built up from fused ten-, five- (lactone) and three-membered (epoxide) rings. The internal double bond in the ten-membered ring has the cis geometry (i.e. it is the E isomer). The lactone ring has an envelope-type conformation, with the (chiral) C atom opposite the lactone O atoms as the flap atom. In the crystal, O—H...O hydrogen bonds link the molecules into chains parallel to the b-axis direction

Crystal structure of 4,5-bis(3,4,5-trimethoxyphenyl)-2H-1,2,3-triazole methanol monosolvate

The title compound, C20H23N3O6·CH3OH, was synthesized by [3 + 2] cycloaddition of (Z)-2,3-bis(3,4,5-trimethoxyphenyl)acrylonitrile with sodium azide and ammonium chloride in DMF/water. The central nitrogen of the triazole ring is protonated. The dihedral angles between the triazole ring and the 3,4,5-trimethoxyphenyl ring planes are 34.31 (4) and 45.03 (5)°, while that between the 3,4,5-trimethoxyphenyl rings is 51.87 (5)°. In the crystal, the molecules, along with two methanol solvent molecules are linked into an R44(10) centrosymmetric dimer by N—H...O and O—H...N hydrogen bonds

Comparison of crystal structures of 4-(benzo[b]thiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)-2H-1,2,3-triazole and 4-(benzo[b]thiophen-2-yl)-2-methyl-5-(3,4,5-trimethoxyphenyl)-2H-1,2,3-triazole

The title compound, C19H17N3O3S (I), was prepared by a [3 + 2]cycloaddition azide condensation reaction using sodium azide and l-proline as a Lewis base catalyst. N-Methylation of compound (I) using CH3I gave compound (II), C20H19N3O3S. The benzothiophene ring systems in (I) and (II) are almost planar, with r.m.s deviations from the mean plane = 0.0205 (14) in (I) and 0.016 (2) Å in (II). In (I) and (II), the triazole rings make dihedral angles of 32.68 (5) and 10.43 (8)°, respectively, with the mean planes of the benzothiophene ring systems. The trimethoxy phenyl rings make dihedral angles with the benzothiophene rings of 38.48 (4) in (I) and 60.43 (5)° in (II). In the crystal of (I), the molecules are linked into chains by N—H...O hydrogen bonds with R21(5) ring motifs. After the N-methylation of structure (I), no hydrogen-bonding interactions were observed for structure (II). The crystal structure of (II) has a minor component of disorder that corresponds to a 180° flip of the benzothiophene ring system [occupancy ratio 0.9363 (14):0.0637 (14)]

Crystal structure of 4,5-bis(3,4,5-trimethoxyphenyl)-2 H

The title compound, C20H23N3O6·CH3OH, was synthesized by [3 + 2] cycloaddition of (Z)-2,3-bis(3,4,5-trimethoxyphenyl)acrylonitrile with sodium azide and ammonium chloride in DMF/water. The central nitrogen of the triazole ring is protonated. The dihedral angles between the triazole ring and the 3,4,5-trimethoxyphenyl ring planes are 34.31 (4) and 45.03 (5)°, while that between the 3,4,5-trimethoxyphenyl rings is 51.87 (5)°. In the crystal, the molecules, along with two methanol solvent molecules are linked into an R44(10) centrosymmetric dimer by N—H...O and O—H...N hydrogen bonds