Mavurapu Satyanarayana
Rutgers University
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Bioorganic & Medicinal Chemistry Letters | 2008
Mavurapu Satyanarayana; Suzanne G. Rzuczek; Edmond J. LaVoie; Daniel S. Pilch; Angela Liu; Leroy F. Liu; Joseph E. Rice
The synthesis of a 24-membered macrocyclic hexaoxazole via ring-closing metathesis is described. The target compound selectively stabilizes G-quadruplex DNA with no detectable stabilization of duplex DNA. An MTT cytotoxicity assay indicated that this unsaturated macrocyclic hexaoxazole exhibits significant cytotoxicity toward P388, RPMI 8402, and KB3-1 cell lines with IC50 values of 45, 25, and 38 nM, respectively.
Bioorganic & Medicinal Chemistry Letters | 2010
Mavurapu Satyanarayana; Young Ah Kim; Suzanne G. Rzuczek; Daniel S. Pilch; Angela A. Liu; Leroy F. Liu; Joseph E. Rice; Edmond J. LaVoie
A series of 24-membered macrocyclic hexaoxazoles containing one or two aminoalkyl substituents was synthesized and evaluated for cytotoxicity and for their ability to selectively stabilize G-quadruplex DNA and RNA. The most cytotoxic analog 4a, with IC(50) values of 25 and 130 nM using KB3-1 and RPMI 8402 cells, is efficacious in vivo in athymic nude mice with a human tumor xenograft from the breast cancer cell line MDA-MB-435.
Journal of Medicinal Chemistry | 2012
Alok K. Verma; Himanshu Singh; Mavurapu Satyanarayana; Swayam Prakash Srivastava; Priti Tiwari; Amar Bahadur Singh; Anil Kumar Dwivedi; Shio Kumar Singh; Mukesh Srivastava; Chandishwar Nath; Ram Raghubir; Arvind K. Srivastava; Ram Pratap
The hybrid congeners 62-90 of 6- and 7-hydroxyflavones with aminopropanol have been synthesized and evaluated for their antidiabetic activity in sucrose-challenged low-dosed streptozotocin (STZ)-induced diabetic rats and db/db mice. The optical enantiomers 70a, 70b, 90a, and 90b of two congeners 70 and 90 exhibiting consistent antidiabetic and antidyslipidemic activities were also prepared, and their antidiabetic activity results indicate its association mainly with S isomers. These compounds also lower cholesterol and TG profiles while improving high-density lipoprotein cholesterol to CHOL ratio in db/db mice. The bioavailability of compound 70 and its isomer varies between 27 and 29% whereas that of the more polar compound 90a is poor as determined in rat by oral and intraperitoneal administrations.
Bioorganic & Medicinal Chemistry | 2008
Wei Feng; Mavurapu Satyanarayana; Liang Cheng; Angela Liu; Yuan Chin Tsai; Leroy F. Liu; Edmond J. LaVoie
Several N-alkyl and N,N-dialkyl 5H-8,9-dimethoxy-5-(2-aminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-ones have been identified as topoisomerase I-targeting agents with potent antitumor activity. In the present study, the impact on biological activity of substitution of a trifluoromethyl, cyano, aminocarbonyl, or ethynyl group on a N-methyl substituent of N,N-dimethyl-, N-methyl-N-ethyl-, and N-methyl-N-isopropyl 5H-8,9-dimethoxy-5-(2-aminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-ones was assessed.
European Journal of Medicinal Chemistry | 2009
Wei Feng; Mavurapu Satyanarayana; Yuan Chin Tsai; Angela A. Liu; Leroy F. Liu; Edmond J. LaVoie
Several new TOP1-targeting agents were prepared using as an intermediate the N,N,N-trimethyl quaternary ammonium salt 2 of ARC-111. Direct displacement of the quaternary ammonium group with hydroxide, cyclopropylamine, imidazole, 1H-1,2,3-triazole, alkylethylenediamines, ethanolamine, and polyhydroxylated alkylamines provides a convenient means for furthering insight into the structure-activity relationships within this series of non-camptothecin TOP1-targeting agents. The relative TOP1-targeting activities and cytotoxicities were evaluated in RPMI8402 and P388 cells and their camptothecin-resistant variants. Their potential to serve as substrates for the efflux transporters MDR1 and BCRP, which are associated with multidrug resistance, was also assessed.
Bioorganic & Medicinal Chemistry | 2009
Wei Feng; Mavurapu Satyanarayana; Yuan Chin Tsai; Angela A. Liu; Leroy F. Liu; Edmond J. LaVoie
2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine and a few of its 12-substituted analogs are active as TOP1-targeting agents. Studies were performed to further evaluate the potential of this series of non-camptothecin TOP1-targeting agents. The influence of a hydroxymethyl, formyl, N,N-dimethylaminomethyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl), and 4-(N,N-dimethylamino)butyl substituent at the 12-position on TOP1-targeting activity and tumor cell growth was evaluated. In addition, the relative pharmacologic activities of the 12-carboxamide analog, as well as its N-methyl and N,N-dimethyl derivatives were assessed.
Bioorganic & Medicinal Chemistry | 2008
Wei Feng; Mavurapu Satyanarayana; Yuan Chin Tsai; Angela A. Liu; Leroy F. Liu; Edmond J. LaVoie
Several 11-substituted benzo[i]phenanthridine derivatives were synthesized, and their TOP1-targeting activity and cytotoxicity were assessed. Comparative data indicate that TOP1-targeting was often the primary molecular target associated with their cytotoxicity. Several 11-aminoalkyl derivatives, 11-aminocarboxy derivatives as well as the 11-[(2-dimethylamino)ethyl]carboxamide of 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine were synthesized and did exhibit considerable cytotoxicity with IC(50) values ranging from 20 to 120 nM in the human lymphoblast tumor cell line RPMI8402.
Bioorganic & Medicinal Chemistry Letters | 2008
Wei Feng; Mavurapu Satyanarayana; Yuan Chin Tsai; Angela A. Liu; Leroy F. Liu; Edmond J. LaVoie
Several new TOP1-targeting agents were prepared using as intermediates the N,N,N-trimethyl quaternary ammonium salts of either ARC-111 or its 12-aza analog (ARC-31), 3 and 4, respectively. Direct displacement of the quaternary ammonium group with water, imidazole, alkylethylenediamines, or polyhydroxylated alkylamines provides a convenient means for furthering the structure-activity relationships associated with these non-camptothecin TOP1-targeting agents.
Bioorganic & Medicinal Chemistry | 2008
Mavurapu Satyanarayana; Wei Feng; Liang Cheng; Angela A. Liu; Yuan Chin Tsai; Leroy F. Liu; Edmond J. LaVoie
Several 11-ethyl-2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-ones with varied functionality on the ethyl substituent have exhibited potent topoisomerase I (TOP1) targeting activity and antitumor activity. The influence of various polar substituents at the 2-position of the 11-ethyl substituent, including N-methylamine, N-isopropylamine, hydroxyl, and hydroxylamino groups, on TOP1-targeting activity and cytotoxicity was assessed. The N-methylamine and N-isopropylamine derivatives were also evaluated as antitumor agents in athymic nude mice with MDA-MB-435 human tumor xenografts. Both compounds were active as antitumor agents upon either parenteral or oral administration.
Molecular Cancer Therapeutics | 2009
Edmond J. LaVoie; Young Ah Kim; Mavurapu Satyanarayana; Suzanna G. Rzuczek; Daniel S. Pilch; Yuan-Chin Tsai; Haiyan Qi; Chao‐Pao Lin; Angela Liu; Leroy F. Liu; Joseph E. Rice
Guanine‐rich nucleic acid sequences are known to adopt G‐quadruplex structures that are stabilized by the formation of guanine tetrads. Compounds that can stabilize G‐quadruplex are known to exhibit cytotoxicity against tumor cells in culture and antitumor activity in mice with human tumor xenografts. Telomestatin, a naturally occurring macrocycle isolated from Streptomyces anulatus , is among the more specific G‐quadruplex stabilizers, binding with high specificity to G‐quadruplex DNA with no detectable binding to either duplex or single‐stranded DNA. Telomestatin has been shown to induce apoptosis of tumor cells in culture and exhibit antitumor activity in mice. The discovery of telomestatin has prompted further studies of other macrocyclic polyoxazoles that can selectively stabilize G‐quadruplex DNA and RNA. Recently the synthesis of the macrocyclic hexaoxazole HXDV was reported by our laboratory. HXDV is a 24‐membered macrocycle that stabilizes G‐quadruplexes. Despite its less complex structure, HXDV is extraordinarily selective at stabilizing G‐quadruplex versus duplex DNA, and is at least as potent as telomestatin as a cytotoxic agent. It has been determined that HXDV binds to a 24mer model human telomeric G‐quadruplex with a stoichiometry of 2:1 via a terminal capping mode of interaction. Surprisingly, HXDV was found to exhibit anti‐proliferative activity against many tumor cells independently of their telomerase status and induces strong apoptosis within 16 hours of treatment. HXDV also inhibited the progression of the cell cycle, resulting in accumulation of cells at the G2/M phase of the cell cycle. Interestingly, these studies revealed that cells were arrested at the M, rather than the G phase of the cell cycle. Unlike tubulin inhibitors, which also arrest cells at M phase, HXDV reduces the expression level of the key M phase regulator Aurora A kinase. In the aggregate, these data suggest that HXDV is a novel M phase blocker, with a possible mode of action distinct from tubulin inhibitors. Both telomestatin and HXDV have limited aqueous solubility. Replacement of one or both isopropyl groups of HXDV with an aminoalkyl side chain alters its phyiscochemical properties and enhances aqueous solubility. We also report herein the synthesis, biophysical evaluation of G‐quadruplex stabilization and selectivity, and cytotoxicity data for more than twenty 24‐membered macrocyclic polyoxazoles that have either one or two alkylamino side chains varying in length from 2–4 methylene units. One of these derivatives exhibits significant antitumor activity with IC 50 values that range from 25 to 70 nM towards human tumor cells. As the citrate salt, the solubility of some of these alkylamino derivatives increased dramatically permitting in vivo studies to evaluation their toxicity and maximum tolerated dose in mice. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C76.