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Synthesis of Aryl‐Substituted Naphthalene‐Linked Pyrrolobenzodiazepine Conjugates as Potential Anticancer Agents with Apoptosis‐Inducing Ability

2011; Wiley; Volume: 6; Issue: 9 Linguagem: Inglês

10.1002/cmdc.201100207

1860-7187

Ähmed Kamal, M. Kashi Reddy, M. Janaki Ramaiah, Y. V. V. Srikanth, Rajender, Vangala Santosh Reddy, G. Bharath Kumar, S. N. C. V. L. Pushpavalli, Indira Bag, Aarti Juvekar, Subrata Sen, Surekha M. Zingde, Manika Pal‐Bhadra,

Cancer Treatment and Pharmacology

Abstract A library of new aryl‐substituted naphthalene C8‐linked pyrrolo[2,1‐ c ][1,4]benzodiazepine (PBD) conjugates with various linker architectures were designed, synthesized, and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. All 32 conjugates show anticancer potential, with some of them exhibiting particularly high activity (0.01–0.19 μ M ). Thermal denaturation studies showed effective DNA binding capacity relative to DC‐81. In assays for biological activity relating to cell‐cycle distribution, these PBD conjugates induce G 0 /G 1 ‐phase arrest and also cause an increase in the levels of p53 and caspase‐9 proteins, followed by apoptotic cell death. One conjugate in particular is the most promising candidate of the series, with the potential to be selected for further studies, either alone or in combination with existing anticancer therapies.