Development of novel conformation-constrained cytotoxic derivatives of cheliensisin A by embedment of small heterocycles

Cheliensisin A is a natural styryl-lactone isolated from Goniothalamus cheliensis Hu in considerably large quantity with putative anticancer activities. However, its poor water solubility and chemical instability have precluded cheliensisin A as a potential drug candidate. To explore the strategy to overcome these problems, 21 novel derivatives of cheliensisin A with different substitutions at C-7 and C-8 positions were designed and synthesized. Inhibition of proliferation against five tumors cell lines indicates that eight new derivatives with embedment of oxazole or oxazoline exhibit improved cytotoxicity on SK-BR-3 and PANC-1, and compounds 2d and 2g show 5–8 folds higher potency than cisplatin. HPLC investigation of representative compounds indicates that oxazole and oxazoline analogs exhibit much improved chemical stability than their natural parent.

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► 21 novel cheliensisin A analogs were synthesized and evaluated against five tumor cell lines.
► Most oxazoline/oxazole containing analogs exhibited improved potency and chemical stability.
► Cis-configuration and reasonable rigid conformation were found to favor the bioactivities.