The adventure of hemicalide: Total synthesis, design of analogues and biological evaluation – AMICAL

Hemicalide is a particularly challenging synthetic target possessing a 46 carbon atom polyketide-type backbone incorporating 21 asymmetric carbons and structural motifs not encountered in other natural products. A convergent and flexible synthetic route toward hemicalide was devised from five subunits, the preparation of which was tackled first. The unprecedented structure of the hydroxylated delta-lactone motifs in hemicalide was an excellent source of inspiration for the development of synthetic methods and innovative strategies that successfully allowed access to the target subunits but also enabled the relative stereochemical assignment of some of the stereocenters in the natural product. The coupling of these latter subunits was then achieved thanks to chemoselective reactions. Their order of execution was carefully optimized to enable the assembly of the entire carbon backbone of a stereoisomer of hemicalide and hence start the investigation of the delicate final deprotection steps. While the project was underway, the biological activation of advanced synthetic intermediates was investigated.

During the course of the project, innovative strategies were developed to elaborate the functionalized delta-lactone containing structural motifs in hemicalide. The devised convergent synthetic plan has enabled the successful assembly of the entire carbon atom backbone of a stereoisomer of hemicalide incorporating 21 controlled stereocenters. The pioneering work accomplished by our consortium provides valuable information regarding the delicate cleavage of the protecting groups, a meaningful comparison of the NMR spectra of our advanced synthetic analog with that of hemicalide and paves the way for future improvement of the synthesis.

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The AMICAL project has led so far to four scientific articles published in peer-reviewed international journals. The results have also been presented on the occasion of eight conferences and oral communications, including one invited lecture to an international symposium devoted to the chemistry of natural products, one knowledge dissemination oral communication and eleven poster presentations.

Natural products play an important role in cancer therapy since they have led to the development of several clinically useful anti-cancer agents. As cancer is a major public health problem and will become the leading cause of death worldwide in the 21st century, the search for novel drugs possessing a completely new mode of action represents an important challenge for the improvement of cancer therapy. During the quest for new and potent cytotoxic compounds from natural sources and in particular marine organisms, a new complex polyketide was recently isolated from extracts of the marine sponge Hemimycale sp., collected in deep water around Torres islands (Vanuatu) in the South Pacific, by French researchers of the CNRS-Pierre Fabre Laboratories joint unit in association with Institut de Recherche pour le Développement (IRD). This new natural product, called hemicalide, was found to be a potent mitotic blocker and to display high anti-proliferative potency against a panel of cancer cell lines at subnanomolar concentrations. Importantly, immuno-cytochemistry studies revealed that hemicalide acted by destabilizing the alpha/beta microtubule network but the mechanism seemed to be different from that observed with known antimitotic antitubulin agents such as taxoids and Vinca alkaloids. However, the remaining amount of hemicalide was not sufficient to support complementary pharmacological evaluation and since harvesting the natural raw material is impossible, chemical synthesis remains the only alternative way to pursue the research. The high interest of the molecule motivates complementary research in the quest for a potential innovative anti-cancer agent: an efficient synthetic route for complete structure and configurational assignment, the preparation of simplified derivatives and the generation of structural activity relationships (SAR) studies that could lead to new targets or mechanisms of action. The teams of organic chemists at the ESPCI and Université Paris Descartes, in collaboration with the CNRS-Pierre Fabre Laboratories joint unit, have embarked on the adventure of hemicalide and decided to join their efforts and expertise in the field of natural products synthesis to achieve the goal of this challenging research project, as part of an ambitious natural product lead optimization program. For synthetic chemists, hemicalide constitutes an absolutely fascinating target due to its complex structure, the presence of 21 stereocenters embedded in a 46 carbon atoms backbone as well as original delta-lactone subunits. Encouraging preliminary results have already been obtained indicating that the goal of this project can reasonably be attained and motivating the development of efficient and innovative synthetic strategies.