The Advance of Anti-Cancer Flexible Heteroarotinoids Compounds

Maryam Mashayekhi, Donghua H. Zhou


Retinoids have clinically proven anti-cancer activities. However, the toxicity of retinoids hinders their application in vivo. Heteroatom substitution on the ring structure in retinoids has resulted in a new class of chemical called heteroarotinoids, which have dramatically lower toxicity. Further modifications have led to flexible heteroarotinoids (Flex-Het). Flex-Hets contain a flexible linker between the heteroatom ring and aryl ring. Among all Flex-Hets, SHetA2, which contains a sulfur heteroatom and a thiourea linker, has been the most promising compound with the highest anti-cancer activity until recently. It has been shown effective against all of over 60 cancer cell lines in the US National Cancer Institute. It is a candidate for clinical trials for the treatment of ovarian cancer. SHetA2 induces both intrinsic (mitochondrial mediated) and extrinsic (death receptor mediated) apoptosis pathways in cancer cells with low toxicity and differential activity against malignant versus normal cells. Heat shock protein HSPA9 (mortalin), which interacts with the tumor protein p53, has been found to be the receptor protein of SHetA2. Binding of SHetA2 to mortalin interrupts p53-mortalin interaction, releasing protein p53 to nucleus where it initiates apoptosis. In this article, the chemistry evolution, anti-cancer activity, biological mechanism, and development of better analogues of Flex-Hets are reviewed.


Cancer therapeutics; Small-molecule drugs; Toxicity; Mitochondria; Mortalin; SHetA2

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