Novel N-Methylated Cyclodepsipeptide Prodrugs for Targeted Cancer Therapy

Abstract

Coibamide A (1) is a highly N-methylated cyclodepsipeptide with low nanomolar antiproliferative activities against various cancer cell lines. In previous work, we discovered a simplified analogue, [MeAla3-MeAla6]-coibamide (1a), which exhibited the same inhibitory abilities as coibamide A. Herein, to reduce the whole-body toxicity and improve the solubility of 1a, two novel peptide−drug conjugates RGD-SS-CA (2) and RGD-VC-CA (3) were designed, synthesized, and evaluated. Composed of cyclodepsipeptide 1a, a tumor-homing RGD motif, and a conditionally labile linker, the conjugates are expected to release 1a tracelessly in specific tumor microenvironments. Compared with RGD-VC-CA (3), RGD-SS-CA (2) proved to be superior in in vitro drug release and cytotoxicity tests. Notably, intravenous injection of RGD-SS-CA (2) into mice-bearing human tumor xenografts induced significant tumor growth suppression with negligible toxicity. Therefore, as a novel prodrug of the coibamide A analogue, conjugate 2 has great potential for further exploration in cancer drug discovery.

Structure–Activity Relationship of Cytotoxic Natural Products from Indonesian Marine Sponges

“…The remarkable cytotoxicity shown by majusculamide D ( 101 ) is obtained from the presence of an alkyl chain, an oxygenated aromatic, and N -methylated amides. The significance of N -methylated amide on peptides has been reported to enhance its membrane permeability, proteolytic stability, and solubility which also increases its oral bioavailability (Chatterjee et al 2008 ; Northfield et al 2014 ; Wu et al 2021 ). The conjecture of the three significant moieties on cytotoxicity against PANC-1 brings possible activities from jasplakinolide ( 89 ), ( +)–jasplakinolide Z 5 ( 91 ), and ( +)–jasplakinolide V ( 92 ), which bears oxygenated aromatics and alkyl chain.…”

Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects

“…In addition, analog (3) inhibited tumor growth in the human MDA-MB-231 xenograft mouse model without presenting significant weight loss or side effects at the dose evaluated [ 66 ]. Furthermore, a stimuli-responsive peptide–drug conjugate (PDC) composed of a tumor-homing peptide with the cRGDyK sequence (cyclic RGD), the synthetic derivative (3), and a reduction-cleavable disulfide linker suppressed tumor growth in the A549 xenograft mouse model with negligible toxicity [ 68 ].…”

Design of Coibamide A Mimetics with Improved Cellular Bioactivity

“…For the application of these promising inhibitors to drug discovery, considerable efforts have been devoted to their medicinal chemistry studies. 25 − 31 On the basis of these insights into Sec61 inhibitors, we investigated the structure–activity relationships (SARs) of CbA ( 1 ) in this study.…”

“…The Sec61 translocon is a component of the protein translocation machinery for the co- and post-translational transport of secreted and transmembrane proteins into the endoplasmic reticulum. , Because the Sec61 channel-mediated translocation of regulatory and pathogenetic proteins, such as adhesion molecules and viral proteins, is involved in the pathological process, Sec61 is a potential molecular target for anticancer and anti-infective agents. , To date, there have been several Sec61 inhibitors reported, , including apratoxin A, , decatransin, eeyarestatin I, , HUN-7293/pestahivin, − ipomoeassin F, and mycolactone A and B (Figure S1). For the application of these promising inhibitors to drug discovery, considerable efforts have been devoted to their medicinal chemistry studies. − On the basis of these insights into Sec61 inhibitors, we investigated the structure–activity relationships (SARs) of CbA ( 1 ) in this study.…”