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High-throughput synthesis and screening of platinum drug candidates
C J Ziegler1, A P Silverman, S J Lippard
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139, USA.
Abstract:
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.
Insights
A new strategy rapidly identifies platinum anticancer drugs. This approach screens thousands of compounds, discovering new drug candidates with potential to treat more tumors and reduce toxicity compared to existing treatments.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Oncology
Background:
- Platinum-based chemotherapy is a cornerstone of cancer treatment.
- Current platinum drugs face limitations including resistance and toxicity.
- Improved platinum drug candidates are needed to broaden efficacy and reduce side effects.
Purpose of the Study:
- To develop a novel strategy for rapid platinum drug discovery.
- To identify novel platinum compounds with efficacy comparable to cisplatin.
- To discover platinum drug candidates with potential for increased tumor spectrum or reduced toxicity.
Main Methods:
- Automated synthesis of platinum drug candidates utilizing the trans effect or silver chloride precipitation.
- High-throughput screening of over 3,600 reaction products using a fluorescent resonance energy transfer (FRET) assay.
- Inhibition of beta-lactamase transcription in BlaM HeLa cells monitored via CCF2/AM dye cleavage.
Main Results:
- Three synthetic routes yielded promising platinum drug candidates.
- Four distinct platinum species were identified among the reaction products.
- Three known cisplatin analogs and one novel compound, cis-[ammine(2-amino-3-picoline)PtCl2], were discovered.
Conclusions:
- The developed strategy enables rapid preparation and screening of platinum anticancer drug candidates.
- This approach represents a significant proof of principle for efficient drug discovery.
- The identified novel compound offers a new avenue for platinum-based antitumor drug development.