Design, synthesis, and biological evaluation of (E)-styrylbenzylsulfones as novel anticancer agents.
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.
Reddy
M V Ramana
MV
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, Pennsylvania 19140-5101, USA. rreddy@temple.edu
Mallireddigari
Muralidhar R
MR
Cosenza
Stephen C
SC
Pallela
Venkat R
VR
Iqbal
Nabisa M
NM
Robell
Kimberly A
KA
Kang
Anthony D
AD
Reddy
E Premkumar
EP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D013343:Styrenes; D013450:Sulfones