Discovery of substituted N-phenyl nicotinamides as potent inducers of apoptosis using a cell- and caspase-based high throughput screening assay

Journal of Medicinal Chemistry

Volumn 46, Issue 12, 2003, Pages 2474-2481

  Cai, Sui Xiong ^a   Nguyen, Bao ^a   Jia, Shaojuan ^a   Herich, John ^a   Guastella, John ^a   Reddy, Sanjeeva ^a   Tseng, Ben ^a   Drewe, John ^a   Kasibhatla, Shailaja ^a  

^a Maxim Pharmaceuticals Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 METHYL N (4 METHOXY 2 NITROPHENYL)PYRIDINE 3 CARBOXAMIDE; ANTINEOPLASTIC AGENT; CASPASE; GLYCOPROTEIN P; N (4 ETHOXY 2 NITROPHENYL)PYRIDINE 3 CARBOXAMIDE; N (4 METHOXY 2 NITROPHENYL)PYRIDINE 3 CARBOXAMIDE; N PHENYLNICOTINAMIDE DERIVATIVE; PACLITAXEL; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL CYCLE G2 PHASE; CONTROLLED STUDY; DRUG POTENCY; DRUG SCREENING; ENZYME ACTIVATION; ENZYME ASSAY; HUMAN; HUMAN CELL; IN VITRO STUDY; POLYMERIZATION;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CASPASE 3; CASPASES; DRUG SCREENING ASSAYS, ANTITUMOR; FLOW CYTOMETRY; HUMANS; NIACINAMIDE; STRUCTURE-ACTIVITY RELATIONSHIP; TUBULIN; TUMOR CELLS, CULTURED;

EID: 0038778278     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0205200     Document Type: Article

References (22)

1. Reed, J. C.; Tomaselli, K. J. Drug Discovery Opportunities From Apoptosis Research. Curr. Opin. Biotechnol. 2000, 11, 586-592.
2. Reed, J. C. Dysregulation of Apoptosis in Cancer. J. Clin. Oncol. 1999, 17, 2941-2953.
3. Robertson, G. S.; Crocker, S. J.; Nicholson, D. W.; Schulz, J. B. Neuroprotection by the Inhibition of Apoptosis. Brain Pathol. 2000, 10, 283-292.
4. Leung, D.; Abbenante, G.; Fairlie, D. P. Protease Inhibitors: Current Status and Future Prospects. J. Med. Chem. 2000, 43, 305-41.
5. Thornberry, N. A. Caspases: Key Mediators of Apoptosis. Chem. Biol. 1998, 5, R97-R103.
6. Kolenko, V. M.; Uzzo, R. G.; Bukowski, R.; Finke, J. H. Caspase-Dependent and -Independent Death Pathways in Cancer Therapy. Apoptosis 2000, 5, 17-20.
7. (a) Simoni, D.; Invidiata, F. P.; Rondanin, R.; Grimaudo, S.; Cannizzo, G.; Barbusca, E.; Porretoo, F.; D'Alessandro, N.; Tolomeo, M. Structure-Activity Relationship Studies of Novel Heteroretinoids: Induction of Apoptosis in the GL-60 Cell Line by a Novel Isoxazole-Containing Heteroretinoid. J. Med. Chem. 1999, 42, 4961-4969.
8. 2(amine)-(isopropylamine)] Compounds. Cytotoxic Activity and Apoptosis Induction in ras-Transformed Cells. J. Med. Chem. 1999, 42, 4264-4268.
9. (c) Simoni, D.; Roberti, M.; Invidiata, F. P.; Rondanin, R.; Baruchello, R.; Malagutti, C.; Mazzali, A.; Rossi, M.; Grimaudo, S.; Capone, F.; Dusonchet, L.; Meli, M.; Raimondi, M. V.; Landino, M.; D'Alessandro, N.; Tolomeo, M.; Arindam, D.; Lu, S.; Benbrook, D. M. Heterocycle-Containing Retinoids. Discovery of a Novel Isoxazole Arotinoid Possessing Potent Apoptotic Activity in Multidrug and Drug-Induced Apoptosis-Resistant Cells. J. Med. Chem. 2001, 44, 2308-2318.
10. (d) Jakobsen, C. M.; Denmeade, S. R.; Isaacs, J. T.; Gady, A.; Olsen, C. E.; Christensen, S. B. Design, Synthesis, and Pharmacological Evaluation of Thapsigargin Analogues for Targeting Apoptosis to Prostatic Cancer Cells. J. Med. Chem. 2001, 44, 4696-4703.
11. Gonzales, A. G.; Silva, M. H.; Padron, J. I.; Leon, F.; Reyes, E.; Alvarez-Mon, M.; Pivel, J. P.; Quintana, J.; Estevez, F.; Bermejo, J. Synthesis and Antiproliferative Activity of a New Compound Containing an α-Methylene-γ-Lactone Group. J. Med. Chem. 2002, 45, 2358-2361.
12. Weber, E.; Tseng, B. Y.; Drewe, J. A.; Cai, S. X. Methods of Identifying Potentially Therapeutically Effective Antineoplastic Agents with Viable Cultured Cells Having an Intact Cell Membrane and Product by Same. Patent Application No. WO0045165, 2000.
13. Cai, S. X.; Zhang, H.-Z.; Guastella, J.; Drewe, J.; Yang, W.; Weber, E. Design and Synthesis of Rhodamine 110 Derivative and Caspase-3 Substrate for Enzyme and Cell-Based Fluorescent Assay. Bioorg. Med. Chem. Lett. 2001, 11, 39-42.
14. For the preparation of the substrate, please refer to: Cai, S. X.; Keana, J. F. W.; Drewe, J. A.; Zhang, H.-Z. Fluorogenic or Fluorescent Reporter Molecules and Their Applications for Whole-Cell Fluorescence Screening Assays for Caspases and Other Enzymes and the Use Thereof. US Patent No. 6, 335, 429, column 116, example 25, column 117, example 30 and 31, 2002.
15. McGovern, S. L.; Caselli, E.; Grigorieff, N.; Shoichet, B. K. A Common Mechanism Underlying Promiscuous Inhibitors From Virtual and High-Throughput Screening. J. Med. Chem. 2002, 45, 1712-1722.
16. Wood, K. W.; Cornwell, W. D.; Jackson, J. R. Past and Future of the Mitotic Spindle as An Oncology Target. Curr. Opin. Pharmacol. 2001, 1, 370-377.
17. Rubenstein, S. M.; Baichwal, V.; Beckmann, H.; Clark, D. L.; Frankmoelle, W.; Roche, D.; Santha, E.; Schwender, S.; Thoolen, M.; Ye, Q.; Jaen, J. C. Hydrophilic, Pro-Drug Analogues of T138067 are Efficacious in Controlling Tumor Growth In Vivo and Show a Decreased Ability to Cross the Blood Brain Barrier. J. Med. Chem. 2001, 44, 3599-3605.
18. Jordan, M. A. Mechanism of Action of Antitumor Drugs that Interact with Microtubules and Tubulin. Curr. Med. Chem. Anticancer Agents 2002, 2, 1-17.
19. Kaye, S. B. Multidrug Resistance: Clinical Relevance in Solid Tumors and Strategies For Circumvention. Curr. Opin. Oncol. 1998, 10, S15-19.
20. Shan, B.; Medina, J. C.; Santha, E.; Frankmoelle, W. P.; Chou, T. C.; Learned, R. M.; Narbut, M. R.; Stott, D.; Wu, P.; Jaen, J. C.; Rosen, T.; Timmermans, P. B.; Beckmann, H. Selective Covalent Modification of Beta-Tubulin Residue Cys-239 by T138067, an Antitumor Agent with In Vivo Efficacy Against Multidrug-Resistant Tumors. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5686-5691.
21. (a) Medina, J. C.; Roche, D.; Shan, B.; Leaner, R. M.; Frankmoelle, W. P.; Clark, D. L.; Rosen, T.; Jaen, J. C. Novel Halogenated Sulfonamides Inhibit the Growth of Multidrug Resistant MCF-7/ADR Cancer Cells. Bioorg. Med. Chem. Lett. 1999, 9, 1843-1846.
22. (b) Medina, J. C.; Shan, B.; Beckman, H.; Farrell, R. P.; Clark, D. L.; Learned, M.; Roche, D.; Li, A.; Baichwal, V.; Case, C.; Baeuerle, P. A.; Rosen, T.; Jaen, J. C. Novel Antineoplastic Agents with Efficacy Against Multidrug Resistant Tumor Cells. Bioorg. Med. Chem. Lett. 1998, 8, 2653-2656.