Reniochalistatin E, is a natural cyclic peptide from a marine sponge, Reniochalina stalagmitis, that was found to be cytotoxic against myeloma (RPMI-8226, IC50 of 4.9 μM), gastric (MGC-803, IC50 of 9.7 μM), and ovarian (HeLa, IC50 of 17.3 μM) cancer. Our laboratory completed the first total synthesis of Reniochalistatin E in 15 steps with 5% yield overall. Compared to the natural compound, the synthetic compound showed very similar cytotoxicity in myeloma (RPMI-8226, IC50 of 4.5 μM) and ovarian cancer (HeLa, IC50 of 16.9 μM). We are now interested in harnessing this molecule as a targeting agent against multiple myeloma. To do this, we hypothesize a covalent conjugation of 6-thiopurine (6TP) through a disulfide linkage will allow for targeted delivery. 6TP has been a primary anti-metabolite used to treat blood cancers since 1952. However, there are dosage limits for 6TP treatments due to severe cytotoxicity; including bilirubin, jaundice, and hepatotoxicity. Our laboratory has been interested in reapplying this molecule in ways that can reduce this off-target toxicity. A potential method to increase effectiveness and decrease dosage is to target the cancer cells with an appropriate drug delivery vehicle. We hypothesize that 6TP can be attached to a cysteine residue positioned where tryptophan resides on Reniochalistatin E and still retain activity because this was previously proven by substituting phenylalanine in the same position. After 6TP incorporation to Reniochalistatin E, in house in vitro testing will assess changes in cellular uptake and accumulation. The results from this research will serve as a guide for future syntheses of novel drug delivery systems for blood cancer treatment. To be presented is the construction of the phenylalanine analog and its biological evaluation, and as well as efforts towards a cysteine analog and potential drug conjugation and evaluation.

Synthetic modification of Reniochalistatin E to enhance drug delivery systems in cancer therapy

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.