High-throughput synthesis and screening of platinum drug candidates.
Platinum drugs play an important role in the treatment of cancer, but there is room for improvement. Here we present a new platinum drug-discovery strategy to identify compounds having efficacy equivalent to that of cisplatin with the expectation that some may increase the spectrum of treatable tumors and/or reduce dose-limiting toxicity. Platinum drug candidates were generated through the use of automated synthesis, taking advantage either of the trans effect or by using silver chloride precipitation to activate the starting materials. Reaction products were screened for activity in a high-throughput transcription assay and the most promising candidates characterized. Over 3,600 reaction products were screened for their ability to inhibit transcription of beta-lactamase in the BlaM HeLa cell line by monitoring cleavage of a lactam ring linking the two halves of a fluorescent resonance energy transfer (FRET) dye, CCF2/AM. From this screen, three reactions produced good candidates, and four species were identified among these reaction products. Three of the compounds, cis-[(isopropylamine)2PtCl2], cis-[(cyclobutylamine)2PtCl2], and cis-[ammine(cyclobutylamine)PtCl2], have been previously determined to be active cisplatin analogs. The fourth compound, cis-[ammine(2-amino-3-picoline)PtCl2], represents a new kind of antitumor drug candidate similar to ZD0473, a recently reported analog. The discovery of these compounds represents an important proof of principle that platinum anticancer drug candidates can be rapidly prepared and screened in this manner.
Ziegler
C J
CJ
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139, USA.
Silverman
A P
AP
Lippard
S J
SJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D017671:Platinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D017671:Platinum Compounds