Methyl scanning approach for enhancing the biological activity of the linear peptidic natural product, efrapeptin C.

Efrapeptin C (1a) is a large peptidic natural product comprising a 15-mer linear sequence and exerts potent anticancer activity by inhibiting mitochondrial FF-ATP synthase. Residues 1-6 and 9-15 of 1a fold into two 3-helical domains and interact with ATP synthase, while the central β-Ala-7-Gly-8 region functions as a flexible linker of the two domains. To enhance the function of 1a by minimally modifying its structure, we envisioned attaching one small methyl group to the β-Ala-7-Gly-8 and designed six methylated analogues 1b-1g, differing only in the position and configuration of the methyl group.

Gramicidin A accumulates in mitochondria, reduces ATP levels, induces mitophagy, and inhibits cancer cell growth.

Gramicidin A (1) is a linear 15-mer peptidic natural product. Because of its sequence of alternating d- and l-chirality, 1 folds into a β-helix in a lipid bilayer and forms a head-to-head dimer to function as a transmembrane channel for monovalent cations (H, Na, and K). The potent anticancer activity of 1 was believed to be mainly attributed to the free ion diffusion across the plasma membrane.

Total Synthesis of Crotophorbolone.

The complex ABC-tricyclic structure of crotophorbolone, a derivative of the tigliane diterpenoids, was assembled by coupling of simple fragments. The six-membered C-ring fragment, having five contiguous stereocenters, was stereoselectively constructed from (R)-carvone. After attachment of the five-membered A-ring through the π-allyl Stille coupling reaction, the α-alkoxy bridgehead radical reaction effected the endo-cyclization of the seven-membered B-ring by forming the sterically congested bond at C9 and C10 stereospecifically and stereoselectively, respectively.