Graduate Thesis Or Dissertation


Studies toward the synthesis of coibamide A and analogues Public Deposited

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  • Coibamide A is a highly methylated cyclic depsipeptide isolated from Panamanian marine filamentous cyanobacteria as part of an International Cooperative Biodiversity Groups (ICBG) program based in Panama. This structurally unique agent exhibits potent cancer cell toxicity with an unprecedented selectivity profile in the National Cancer Institute (NCI) 60 cell line panel, possibly through a novel mechanism as suggested by "COMPARE negative" results. Therefore, it is considered a promising lead agent in cancer drug discovery. Although field recollections have provided a few milligrams of coibamide A, the amount obtained is still insufficient for extensive biological testing. The producing strain has recently been cultured, but coibamide yields are very low and the growth rate is slow. Chemical synthesis of coibamide A is central to further biological testing and potential clinical development, and has become the major focus of my work. A macrocycle-side chain strategy was originally proposed for the synthesis of coibamide A. It was unsuccessful, however, due to the difficulties trying to couple the macrocycle and side chain together at the last step. To solve this problem, a modified macrocycle – side chain stragety was proposed. Coibamide A was disconnected into two other subunits: the N-MeLeu-macrocycle and the "tripeptide" side chain. The reason for this modification was that the secondary amine of N-MeLeu, with some distance from the bulky macrocycle, should be spatially more availalbe for the final step to couple with the side chain "tripeptide". This new strategy was able to generate "synthetic coibamide" in a moderate yield, this compound, however, was not the natural product coibamide A according to HPLC, 1H NMR and activity test. By Marfey's analysis, we found that in this synthetic coibamide A, no N,O-diMe L-Ser was detected and only its D-counterpart was present, which indicated an unusual L-to-D inversion during coupling reactions. Because it was very difficult to overcome this unexpected inversion during this strategy, a third scheme, the Y-Strategy, was proposed. For the Y-strategy, instead of building the macrocycle first, we coupled the side chain with a macrocycle tripeptide first to afford a linear heptapeptide. Then the ester bond between the hydroxy of N-MeThr and carboxy of N-MeAla (of a tetrapeptide) was built to generate the full-size "Y-structure", which is then deprotected and cyclized to produce the target molecule coibamide A. While the heptapeptide was synthesized sucessfully, the ester bond formation reaction to generate the Y-structure did not happen. Although the Y-strategy did not eventually yield coibamide, it is the most convergent and efficient strategy so far. Because the pharmacological data for coibamide A suggest a unique mechanism and no natural coibamide analogues were separated from the field collections or cultures, the synthesis of coibamide analogues is also extremely valueable for activity and mechanism studies and becomes part of our synthetic effort. The analogues should reasonably resemble the structure of coibamide A, and be easier to be achieved synthetically compared to coibamide A itself. Two families of analogues were designed: the N-desmethyl coibamide family (most or all of the N-methylated amino acid components were replaced by regular amino acids) and the N-MeSer coibamide family (the junction N-MeThr was changed to N-MeSer). Per-N-desmethyl coibamide and several other analogues from the first family were synthesized by the modified macrocycle - side chain strategy, however, none of them exhibits any activity against the testing cell lines. Attempt to per-methylate these compounds also failed due to decomposition of substrates under basic conditions. N-MeSer-coibamide was successfully synthesized through the Y-strategy and purified by HPLC. Cell toxicity has been observed in the activity test, although the potency was several hundred times lower than the natural coibamide A. The synthetic process of N-MeSer coibamide should be optimized for better yields and easier purification as the focus of next stage.
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