Design, Synthesis, and Conformation–Activity Study of Unnatural Bridged Bicyclic Depsipeptides as Highly Potent Hypoxia Inducible Factor-1 Inhibitors and Antitumor Agents

Abstract

By carrying out structural modifications based on the bicyclic peptide structure of echinomycin, we successfully synthesized various powerful antitumor derivatives. The ring conformation in the obtained compounds was restricted by cross-linking with an unnatural bond. The prepared derivatives were demonstrated to strongly suppress the hypoxia inducible factor (HIF)-1 transcriptional activation and hypoxia induction of HIF-1 protein expression. Particularly, alkenebridged derivative 12 exhibited remarkably potent cytotoxicity (IC 50 = 0.22 nM on the MCF-7 cell line) and HIF-1 inhibition (IC 50 = 0.09 nM), which considerably exceeded those of echinomycin. Conformational analyses and molecular modeling studies revealed that the biological activities were enhanced following restriction of the conformation by cross-linking through a metabolically stable and rigid bridge bond. In addition, we proposed a new globular conformation stabilized by intramolecular π stacking that can contribute to the biological effects of bicyclic depsipeptides. The developments presented in the current study serve as a useful guide to expand the chemical space of peptides in drug discovery.

Total Synthesis of Echinomycin and Its Analogues

“…Of interest is the cytotoxic activity of 4 . The sulfide 4 was 4-fold less cytotoxic but still potent, and the result was in good accordance with those reported by Nagasawa’s group . In conjunction with the fact that 22 retained a potent activity, it is suggested that the exo -cyclic methylthio group of 1 does not affect the cytotoxic activity against MIA PaCa-2 cells.…”

“…The late-stage construction of the thioacetal moiety was planned via Pummerer rearrangement of the sulfide 4 . Considering that 4 is a C 2-symmetrical bicyclic octadecadepsipeptide bridged with a sulfide linkage, simultaneous cyclization, as well as two-directional elongation of the peptide chains, was applied to minimize the synthetic steps to 4 . Thus, we disconnected 4 to the branched octapeptide 5 at the amide bonds linking d -Ser and l -Ala residues, and 5 was disconnected to the sulfide 6 , the ester 7 , and Boc- l -Ala ( 8 ).…”

An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor

“…Phase II clinical trials on echinomycin have been performed in patients with metastatic disease, but no significant clinical responses were observed in a phase II study [ 95 , 96 ]. Modulation of the echinomycin structure could be a beneficial approach to improve the therapeutic effect [ 97 ]. It has already been confirmed that liposomal-echinomycin provides significantly greater inhibition of primary tumor growth, and only liposome-formulated echinomycin can eliminate established triple-negative breast cancer (TNBC) metastases in a mouse model with MDA-MB-231 tumors [ 98 ].…”

A recyclable covalent triazine framework-supported iridium(iii) terpyridine complex for the acceptorless dehydrogenative coupling of o-aminobenzyl alcohols with ketones to form quinolines

“…Quinolines represent ubiquitous structural motifs which exist widely in naturally occurring products, 1 pharmaceuticals, 2 functional materials, 3 and ligands of organocatalysts and transition metal catalysts. 4 As a result, a range of classical annulation reactions for the construction of quinolines have been developed, such as Skraup, Doebner–von Miller, Conrad–Limpach–Knorr, Pfitzinger, Combes, Riehm, Gould–Jacobs and Friedlander syntheses.…”