Shobanbabu Bommagani

Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin.

A series of novel diarylacrylonitrile and trans-stilbene analogues of resveratrol has been synthesized and evaluated for their anticancer activities against a panel of 60 human cancer cell lines. The diarylacrylonitrile analogues 3b and 4a exhibited the most potent anticancer activity of all the analogues synthesized in this study, with GI50 values of < 10 nM against almost all the cell lines in the human cancer cell panel. Compounds 3b and 4a were also screened against the acute myeloid leukemia (AML) cell line, MV4-11, and were found to have potent cytotoxic properties that are likely mediated through inhibition of tubulin polymerization. Results from molecular docking studies indicate a common binding site for 4a and 3b on the 3,3-tubulin heterodimer, with a slightly more favorable binding for 3b compared to 4a; this is consistent with the results from the microtubule assays, which demonstrate that 4a is more potent than 3b in inhibiting tubulin polymerization in MV4-11 cells. Taken together, these data suggest that diarylacrylonitriles 3b and 4a may have potential as antitubulin therapeutics for treatment of both solid and hematological tumors.

Synthesis and evaluation of a series of quinolinyl trans-cyanostilbene analogs as anticancer agents

A series of novel trans-2-quinolyl-, 3-quinolyl- and 4-quinolyl cyanostilbene derivatives were synthesized as analogs of combretastatin A-4 (CA-4), and evaluated for anticancer activity against a panel of 60 human cancer cell lines. The quinolin-2-yl and quinolin-3-yl analogs containing trimethoxyphenyl (10 and 16, respectively) or dimethoxyphenyl (12 and 18, respectively) moieties showed growth inhibition against all the cancer cell lines in the panel, with GI50 values generally <1 μM. Quinolin-2-yl-analog 10 exhibited potent growth inhibition against MDA-MB-435 melanoma and NCI-H522 non-small cell lung cancer line with GI50 values of 33 nM and 37 nM respectively. Quinolin-2-yl-analog 12 showed potent growth inhibition against NCI-H522 non-small cell lung cancer lines with a GI50 value of 94 nM. Quinolin-3-yl-analog 18 exhibited potent growth inhibition against MDA-MB-435 melanoma and NCI-H522 non-small cell lung cancer lines with GI50 values of 53 nM and 69 nM, respectively. Thus, structural modification of the CA-4 molecule has afforded compounds with potential clinical utility in the treatment a variety of different solid tumors.

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

In the crystal structure of (I), the molecules are linked into chains by N—H⋯O hydrogen bonds with (5) ring motifs. After the N-methylation of structure (I), no hydrogen-bonding interactions were observed for structure (II).

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

In the crystal structure of (I), the molecules are linked into chains by N—H⋯O hydrogen bonds with (5) ring motifs. After the N-methylation of structure (I), no hydrogen-bonding interactions were observed for structure (II).

Crystal structure of 4,5-bis-(3,4,5-tri-meth-oxy-phen-yl)-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 R 4 4(10) centrosymmetric dimer by N—H⋯O and O—H⋯N hydrogen bonds.

Crystal structure of (E)-13-{4-[(Z)-2-cyano-2-(3,4,5-tri­meth­oxy­phen­yl)ethen­yl]phen­yl}parthenolide methanol hemisolvate

The title compound, C33H35NO6 [systematic name: (Z)-3-(4-{(E)-[(E)-1a,5-dimethyl-9-oxo-2,3,7,7a-tetrahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-8(1aH,6H,9H,10aH,10bH)-ylidene]methyl}phenyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile methanol hemisolvate], C33H35NO6·0.5CH3OH, was prepared by the reaction of (Z)-3-(4-iodophenyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile with parthenolide [systematic name: (E)-1a,5-dimethyl-8-methylene-2,3,6,7,7a,8,10a,10b-octahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-9(1aH)-one] under Heck reaction conditions. The molecule is built up from fused ten-, five- (lactone) and three-membered (epoxide) rings with a {4-[(Z)-2-cyano-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl}methylidene group as a substituent. The 4-[(Z)-2-cyano-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl group on the parthenolide exocyclic double bond is oriented in a trans position to the lactone ring to form the E isomer. The dihedral angle between the benzene ring of the phenyl moiety and the lactone ring mean plane is 21.93 (4)°.

Evaluation of morphine‐like effects of the mixed mu/delta agonist morphine‐6‐O‐sulfate in rats: Drug discrimination and physical dependence

Morphine‐6‐O‐sulfate (M6S) is as a mixed‐action mu/delta (μ/δ) opioid receptor agonist with high potency and analgesic efficacy. These studies used assays of drug discrimination and schedule‐controlled responding to assess abuse‐liability, tolerance, and physical dependence as compared to morphine in rats. Attempts to train 0.3 mg/kg (IP) M6S from saline failed, but all rats rapidly acquired the discrimination when the training dose was changed to 3.0 mg/kg morphine, and substitution tests showed that morphine and fentanyl both fully substituted for the training dose, M6S and M3A6S (3‐O‐acetyl ester of M6S) only partially substituted, and salvinorin A did not elicit morphine‐like effects. Tolerance to response rate‐decreasing effects was studied in rats administered either 1.0 or 3.0 mg/kg morphine or M6S before food‐reinforced operant sessions. At both unit doses, tolerance to M6S‐elicited rate suppression developed more slowly than tolerance to morphine‐induced reductions in response rates. To assess dependence, rats were maintained on 1.0 mg/kg morphine or 1.0 mg/kg M6S until food‐reinforced response rates were stable for at least 5 days. Rats were then administered saline or increasing doses of the opioid antagonist naltrexone (NTX) (0.3, 1.0, 3.0, or 10.0 mg/kg) in order to determine antagonist‐precipitated withdrawal. NTX precipitated withdrawal was similar in both morphine‐maintained and M6S‐maintained rats. In conclusion, the mixed μ/δ agonist activity of M6S failed to completely protect against the development of physical dependence, but delayed tolerance development to behavioral effects and resulted in decreased morphine‐like subjective effects, perhaps implying a decreased abuse liability over μ agonists.

Crystal structure of (E)-13-(pyrimidin-5-yl)parthenolide.

The title molecule possesses ten-, five- (lactone) and three-membered (epoxide) rings with a pyrimidine group as a substituent. The ten-membered ring displays an approximate chair–chair conformation, while the lactone ring shows a flattened envelope-type conformation.

(E)-13-(2-Bromo­phen­yl)micheliolide

The title compound, C21H23BrO3 [systematic name: (3E,3aS,6Z,9R,9aS,9bS)-3-(2-bromobenzylidene)-9-hydroxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one] was prepared by the reaction of 1-bromo-2-iodobenzene with micheliolide [systematic name: (3aS,R,9aS,9bS,Z)-9-hydroxy-6,9-dimethyl-3-methylene-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one] under Heck reaction conditions. The title compound exhibits intramolecular O—H⋯O hydrogen bonding between the hydroxy group and the lactone ring O atom, forming a ring of graph-set motif S(6). The 2-bromophenyl group is trans to the lactone ring, indicating that this is the E isomer (geometry of the exocyclic C=C bond). The dihedral angle between the benzene ring of the 2-bromophenyl moiety and the mean plane of the lactone ring is 51.68 (7)°.

13-(N,N-Di-methyl-amino)-micheliolide 0.08-hydrate.

The title compound, C17H27NO3·0.08H2O {sytematic name: (3R,3aS,9R,9aS,9bS)-3-[(dimethylamino)methyl]-9-hydroxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one 0.08-hydrate}, exhibits intramolecular O—H⋯O hydrogen bonding to form a ring of graph-set motif S(6). As well as this intramolecular hydrogen bond with the lactone-ring O atom, the hydroxy H atom forms an O—H⋯O hydrogen bond to the low-occupancy partial water molecule [occupancy = 0.078 (2)]. The water molecule is correlated with disorder of the N(CH3)2 group [major–minor occupancy factors are 0.922 (2):0.078 (2)]. The dihedral angle between the mean planes of the trans-fused seven-membered ring and the lactone ring is 4.42 (9)°.