Design, Synthesis, and Biological Evaluation of (E)-Styrylbenzylsulfones as Novel Anticancer Agents

• Published in: Journal of medicinal chemistry Vol. 51; no. 1; pp. 86 - 100
• Main Authors: Reddy, M. V. Ramana, Mallireddigari, Muralidhar R, Cosenza, Stephen C, Pallela, Venkat R, Iqbal, Nabisa M, Robell, Kimberly A, Kang, Anthony D, Reddy, E. Premkumar
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.01.2008; Amer Chemical Soc
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Chemistry, Medicinal; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Mice; Mice, Nude; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Styrenes - chemical synthesis; Styrenes - chemistry; Styrenes - pharmacology; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; Toxicity Tests; CYCLIN-DEPENDENT KINASES; PATHWAYS; APOPTOSIS; GENES; ANTINEOPLASTIC AGENTS; HYDROXYL; INHIBITORS; CELL; Antineoplastic agent; Human; Sulfone; Rodentia; non-small cell lung carcinoma; In vitro; In vivo; Vertebrata; Mammalia; Cell line; Structure activity relation; Mouse; Animal; Styrene derivatives; Vinylic compound; Cell cycle; Phenols; Colon; Mammary gland; Chemical synthesis; Prostate; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701077b

Cell cycle progression is regulated by cyclins and cyclin-dependent kinases, which are formed at specific stages of the cell cycle and regulate the G1/S and G2/M phase transitions, employing a series of “checkpoints” governed by phosphorylation of their substrates. Tumor development is associated with the loss of these checkpoint controls, and this provides an approach for the development of therapeutic agents that can specifically target tumor cells. Here, we describe the synthesis and SAR of a novel group of cytotoxic molecules that selectively induce growth arrest of normal cells in the G1 phase while inducing a mitotic arrest of tumor cells resulting in selective killing of tumor cell populations with little or no effect on normal cell viability. The broad spectrum of antitumor activity in vitro and xenograft models, lack of in vivo toxicity, and drug resistance suggest potential for use of these agents in cancer therapy.