The solid-phase combinatorial synthesis of cyclodepsipeptide destruxin E has been demonstrated. The combinatorial synthesis of cyclization precursors 8 was achieved by using a split and pool method on SynPhase Lanterns. The products were successfully macrolactonized in parallel in the solution phase by using 2-methyl-6-nitrobenzoic anhydride and 4-(dimethylamino)pyridine N-oxide to afford macrolactones 9, and the subsequent formation of an epoxide in the side chain gave 18 member destruxin E analogues 6. Biological evaluation of analogues 6 indicated that the N-MeAla residue was crucial to the induction of morphological changes in osteoclast-like multinuclear cells (OCLs). Based on structure-activity relationships, azido-containing analogues 15 were then designed for use as a molecular probe. The synthesis and biological evaluation of analogues 15 revealed that 15 b, in which the Ile residue was replaced with a Lys(N3 ) residue, induced morphological changes in OCLs at a sufficient concentration, and modification around the Ile residue would be tolerated for attachment of a chemical tag toward the target identification of destruxin E (1).
Combinatorial synthesis and biological evaluation of cyclodepsipeptide destruxin B have been achieved. The cyclization precursors were prepared by solid-phase peptide synthesis via a split and pool method utilizing SynPhase lanterns with colored tags and cogs, followed by cleavage from the polymer-support. Macrolactonization utilizing MNBA-DMAPO in solution-phase was successfully performed in parallel to afford the desired 64-member destruxin analogues in moderate to good yields. Biological evaluation of the synthesized analogues indicated that a MeAla residue for the building block A is required to induce the desired morphological changes in osteoclast-like multinuclear cells (OCLs), and introduction of the substituent at the R(4) position of a proline moiety is tolerated by the morphology and may enable the preparation of a molecular probe for the target identification in the osteoclasts.
Nitensidine A is a guanidine alkaloid isolated from Pterogyne nitens, a common plant in South America. To gain insight into the biological activity of P. nitens-produced compounds, we examined herein their biological effects on osteoclasts, multinucleated giant cells that regulate bone metabolism by resorbing bone. Among four guanidine alkaloids (i.e., galegine, nitensidine A, pterogynidine, and pterogynine), nitensidine A and pterogynine exhibited anti-osteoclastic effects at 10 μM by reducing the number of osteoclasts on the culture plate whereas galegine and pterogynidine did not. The anti-osteoclastic activities of nitensidine A and pterogynine were exerted in a concentration-dependent manner, whereas nitensidine A exhibited an approximate threefold stronger effect than pterogynine (IC50 values: nitensidine A, 0.93 ± 0.024 μM; pterogynine, 2.7 ± 0.40 μM). In the present study, the anti-osteoclastic effects of two synthetic nitensidine A derivatives (nitensidine AT and AU) were also examined to gain insight into the structural features of nitensidine A that exert an anti-osteoclastic effect. The anti-osteoclastic effect of nitensidine A was greatly reduced by substituting the imino nitrogen atom in nitensidine A with sulfur or oxygen. According to the differences in chemical structures and anti-osteoclastic effects of the four guanidine alkaloids and the two synthetic nitensidine A derivatives, it is suggested that the number, binding site, and polymerization degree of isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their anti-osteoclastic effects.
This study demonstrates the synthesis and biological evaluation of destruxin E analogs possessing various functional groups in the α‐hydroxycarboxylic acid moiety. Parallel synthesis of eleven analogs was successfully achieved through solution‐phase peptide synthesis and macrolactonization. Biological evaluation of the synthetic analogs using osteoclast‐like multi nuclear cells (OCLs) revealed that the epoxide group in the side chain of α‐hydroxycarboxylic acid and the orientation of the oxygen atom are essential factors in the desired potent activity that induces morphological changes in OCLs for the inhibition of bone‐resorbing activity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.