Vijayakumar N. Sonar

Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents

A new library of small molecules with structural features resembling combretastatin analogs was synthesized and evaluated for anticancer activity against a panel of 60 human cancer cell lines. Three novel acrylonitrile analogs (5, 6 and 13) caused a significant reduction in cell growth in almost all the cell lines examined, with GI50 values generally in the range 10-100 nM. Based on the structural characteristics of similar drugs, we hypothesized that the cytotoxic activity was likely due to interaction with tubulin. Furthermore, these compounds appeared to overcome cell-associated P-glycoprotein (P-gp)-mediated resistance, since they were equipotent in inhibiting OVCAR8 and NCI/ADR-Res cell growth. Given that antitubulin drugs are among the most effective agents for the treatment of advanced prostate cancer we sought to validate the results from the 60 cell panel by studying the representative analog 6 utilizing prostate cancer cell lines, as well as exploring the molecular mechanism of the cytotoxic action of this analog.

Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway.

Radiation therapy combined with adjuvant hyperthermia has the potential to provide outstanding local-regional control for refractory disease. However, achieving therapeutic thermal dose can be problematic. In the current investigation, we used a chemistry-driven approach with the goal of designing and synthesizing novel small molecules that could function as thermal radiosensitizers. (Z)-(+/-)-2-(1-Benzenesulfonylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol was identified as a compound that could lower the threshold for Hsf1 activation and thermal sensitivity. Enhanced thermal sensitivity was associated with significant thermal radiosensitization. We established the structural requirements for activity: the presence of an N-benzenesulfonylindole or N-benzylindole moiety linked at the indolic 3-position to a 2-(1-azabicyclo[2.2.2]octan-3-ol) or 2-(1-azabicyclo[2.2.2]octan-3-one) moiety. These small molecules functioned by exploiting the underlying biophysical events responsible for thermal sensitization. Thermal radiosensitization was characterized biochemically and found to include loss of mitochondrial membrane potential, followed by mitotic catastrophe. These studies identified a novel series of small molecules that represent a promising tool for the treatment of recurrent tumors by ionizing radiation.

Ceric Ammonium Nitrate (CAN): An Efficient Catalyst for the Coumarin Synthesis via Pechmann Condensation using Conventional Heating and Microwave Irradiation

Abstract An efficient and convenient method for the synthesis of substituted coumarins via Pechmann condensation of different phenols with ethylacetoacetate in the presence of ammonium cerium(IV) nitrate as the catalyst in a solvent- free media using both conventional heating and microwave irradiation.

Synthesis and antitubercular activity of a series of hydrazone and nitrovinyl analogs derived from heterocyclic aldehydes

A series of hydrazone and 3-nitrovinyl analogs of indole-3-carboxaldehydes and related compounds were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37RV in BACTEC 12B medium using the Microplate Alamar Blue Assay (MABA). Several compounds showed inhibitory activity against M. tuberculosis in primary screening assays at a concentration of 6.25 μg/mL; subsequent dose-response studies indicated that the most active compounds, 3d, 3e & 8b, had IC50 values of 5.96, 5.4 & 1.6 μg/mL, respectively. These compounds represent potential leads for the further development of novel antitubercular agents.

Indolyl-quinuclidinols inhibit ENOX activity and endothelial cell morphogenesis while enhancing radiation-mediated control of tumor vasculature

There is a need for novel strategies that target tumor vasculature, specifically those that synergize with cytotoxic therapy, in order to overcome resistance that can develop with current therapeutics. A chemistry‐driven drug discovery screen was employed to identify novel compounds that inhibit endothelial cell tubule formation. Cell‐based phenotypic screening revealed that noncytotoxic concentrations of (Z)‐(±)‐2– (1‐benzenesulfonylindol‐3–ylmethylene)‐1‐azabicyclo[2. 2.2]octan‐3‐ol (analog I) and (Z)‐(±)‐2‐(l‐benzylindol‐3‐ylmethylene)‐1‐azabicyclo[2.2.2]octan‐3‐ol (analog II) inhibited endothelial cell migration and the ability to form capillary‐like structures in Matrigel by ≥70%. The ability to undergo neoangiogenesis, as measured in a window‐chamber model, was also inhibited by 70%. Screening of biochemical pathways revealed that analog II inhibited the enzyme ENOX1 (EC50 = 10 µM). Retroviral‐mediated shRNA suppression of endothelial ENOX1 expression inhibited cell migration and tubule formation, recapitulating the effects observed with the small‐molecule analogs. Genetic or chemical suppression of ENOX1 significantly increased radiation‐mediated Caspase3‐activated apoptosis, coincident with suppression of p70S6K1 phosphorylation. Administration of analog II prior to fractionated X‐irradiation significantly diminished the number and density of tumor microvessels, as well as delayed syngeneic and xenograft tumor growth compared to results obtained with radiation alone. Analysis of necropsies suggests that the analog was well tolerated. These results suggest that targeting ENOX1 activity represents a novel therapeutic strategy for enhancing the radiation response of tumors.—Geng, L., Rachakonda, G., Morre, D. J., Morre, D. M., Crooks, P. A., Sonar, V. N., Roti Roti, J. L., Rogers, B. E., Greco, S., Ye, F., Salleng, K. J., Sasi, S., Freeman, M. L., Sekhar, K. R. Indolyl‐quinuclidinols inhibit ENOX activity and endothelial cell morphogenesis while enhancing radiation‐mediated control of tumor vasculature. FASEB J. 23, 2986–2995 (2009). www.fasebj.org

(Z)-3-(1H-Indol-3-yl)-2-(3-thienyl)acrylonitrile and (Z)-3-[1-(4-tert-butylbenzyl)-1H-indol-3-yl]-2-(3-thienyl)acrylonitrile.

(Z)-3-(1H-Indol-3-yl)-2-(3-thienyl)acrylonitrile, C15H10N2S, (I), and (Z)-3-[1-(4-tert-butylbenzyl)-1H-indol-3-yl]-2-(3-thienyl)acrylonitrile, C26H24N2S, (II), were prepared by base-catalyzed reactions of the corresponding indole-3-carboxaldehyde with thiophene-3-acetonitrile. 1H/13C NMR spectral data and X-ray crystal structures of compounds (I) and (II) are presented. The olefinic bond connecting the indole and thiophene moieties has Z geometry in both cases, and the molecules crystallize in space groups P2(1)/c and C2/c for (I) and (II), respectively. Slight thienyl ring-flip disorder (ca 5.6%) was observed and modeled for (I).

(Z)-2-(1-Phenylsulfonyl-1H-indol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-one and (Z)-(S)-2-(1-phenylsulfonyl-1H-indol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol.

The title compounds, C22H20N2O3S, (I), and C22H22N2O3S, (II), crystallize in space groups P-1 and P2(1)2(1)2(1), respectively. The indole rings are planar and the benzene ring of the phenylsulfonyl group makes a dihedral angle with the mean plane of the indole ring of 90.2 (2) degrees in (I) and 94.0 (2) degrees in (II). In both molecules, the double bond connecting the aza-bicyclic and indole moieties has a Z geometry. Compound (II) was obtained as an enantiomerically pure crystal and has the 3S configuration.

rac -( Z )-2-(2-Thienylmethylene)-1-azabicyclo[2.2.2]octan-3-ol

The asymmetric unit of the racemic form of the title compound, C(12)H(15)NOS, contains four crystallographically independent molecules. The olefinic bond connecting the 2-thienyl and 1-azabicyclo[2.2.2]octan-3-ol moieties has Z geometry. Strong hydrogen bonding occurs in a directed co-operative O-H...O-H...O-H...O-H R(4)(4)(8) pattern that influences the conformation of the molecules. Co-operative C-H...pi interactions between thienyl rings are also present. The average dihedral angle between adjacent thienyl rings is 87.09 (4) degrees.

(Z)-3-(1-Methyl-1H-indol-3-yl)-2-(thiophen-3-yl)acrylonitrile.

The title compound, C16H12N2S, has been synthesized by base-catalyzed condensation of 1-methylindole-3-carboxaldehyde with thiophene-3-acetonitrile. The product assumes an approximately planar Z configuration. The molecule has a thienyl-ring flip disorder.

Synthesis and In Vitro Screening of Novel Heterocyclic Compounds as Potential Breast Cancer Agents

Breast cancer is one of the most common non-cutaneous type of cancer in women in worldwide and a leading cause of cancer-related deaths, and is increasing year by year in almost every areas of the globe. Breast cancer is commonly classified into the following two major types: (1) non-invasive breast cancer (cancer cells are confined within the duct and lobules) and (2) invasive breast cancer (cancer cells invade through the walls of the duct or lobules and infiltrate the surrounding tissues). Various kinds of treatments are available for breast cancer, such as chemotherapy, radiotherapy and hormone therapy (Ragaz, 2009). Many indole derivatives are reported as potent breast cancer agents, such as aplysinopsin analogs and indole-3-carbinols. Aplysinopsins are indole-derived marine natural products. The parent aplysinopsin was isolated for the first time (Kazlauskas, et al, 1977) as the major metabolite of eight Indo-Pacific sponge species, which are representatives of the genus Thorecta. The N-1-unsubstituted aplysinopsins have generated considerable interest due to their potentially useful medicinal properties (Dobroslawa, et al, 2009). Aplysinopsin has been reported as a potent cytotoxic agent against the Kβ-cell line and methyl-aplysinopsins against L-1210 and Kβ-cell lines has been reported as potent cytotoxic agents (Hollenbeak & Schmitz, 1977), and the anticancer activities of aplysinopsin and methyl-aplysinopsins against both 1210and Kβ-cells has also been reported (Kondo et al. 1994). Indole-3-carbinol, a phytochemical derived from cruciferous vegetables such as broccoli and Brussel sprouts, exhibits potent antiproliferative effects against human breast cancer cells and has been shown to decrease metastatic spread of tumors in experimental animals (Brew, et al., 2010). From the above observations and as part of a program for the development of small molecules as potential anticancer treatments (Thirupathi Reddy, et al., 2010 and Narsimha Reddy et al., 2010), we initiated a drug discovery program to identify novel benzylaplysinopsin analogs as potent breast cancer agents. Combretastins are plant products from the South African tree Combretum caffrum. This compound was found to inhibit tubulin polymerization, and competitively inhibit the