Balgacyclamides: efforts towards total synthesis and applications into solving complex biological problems

Abstract

Balgacyclamides are a group of natural products isolated from freshwater cyanobacteria Microcystis aeruginosa EAWAG 251 Gademann and co-workers in 2014. They are macrocyclic polypeptides that can also be identified as cyanobactins. Three natural products that belongs to this family have been reported so far; namely balgacyclamide A-C. Balgacyclamide A and B have reported toxicity towards a chloroquine resistant strain of the malarial parasite Plasmodium falciparum K1 and possessed moderate cytotoxicity towards rat myoblasts with implied capability of penetration into lung and colon cancer cells. Given the interesting cellular penetration ability of balgacyclamides, our laboratory embarked on a journey for the first total synthesis of balgacyclamide A, and B in a convergent synthetic approach to access both the natural products in the same route. A synthetic route was established for accessing the two natural products and two other analogs using commercially available amino acids. Establishing the synthesis route for the two natural product analogs served as a model system for the synthetic route of the actual natural products. Due to the ability of balgacyclamides to penetrate into lung and colon cancer cells, it is envisioned to utilize these molecules to conjugate them with available anticancer drugs with the aim of lowering off-target side effects. Also, a small molecule library has been synthesized using an intermediate of balgacyclamide A, and B synthesis to study their ability to penetrate Gram-negative bacteria through porins. This study reveals many unprecedented properties of small molecules that aid penetration of molecules through porins; the most interesting finding being how the three-dimensional orientation of the molecules affect porin-mediated penetration of small molecules despite having approximately the same physicochemical properties.