Synthesis and Structure–Activity Relationship of Cytotoxic Marine Cyclodepsipeptide IB‐01212 Analogues

Abstract

Several recently discovered marine products have remarkable in vitro and in vivo anticancer profiles against a wide range of tumor cell lines. Some of these compounds are currently in clinical trials. These compounds show complex structures and mechanisms of action of interest. Herein, we describe the preparation of a series of totally synthetic molecules that are structurally related to the natural marine product IB‐01212 and evaluated them as antitumor agents. For this, total solid‐phase syntheses of the products were performed in parallel by two distinct routes: linear synthesis and convergent synthesis. Structural modifications were introduced in several residue positions to afford 21 IB‐01212 analogues for structure–relationship studies. An increase in the number of methyl groups in the macrocycle enhanced cytotoxic activity. Also, the replacement of an ester bond by an amide bond favored antitumor activity against several human cell lines. In addition, the L configuration analogues were more active against all the tumor cell lines than those containing the D configuration. A significant increase in the size and asymmetry of the macrocycle diminished biological activity with respect to that of IB‐01212. These results are of great value for the discovery of new and more effective anticancer agents.

Natural Cyclopeptides as Anticancer Agents in the Last 20 Years

“…The synthetic and SAR studies of IB-01212 demonstrated great cytotoxic significance of its symmetric structure. The N-methylation on the amino acids of IB-01212 were found to enhance its cytotoxic effect, which were corroborating evidence for further discovery and synthesis of new analogs for anticancer drug development [330,331].…”

Solid-Phase Synthesis of NMe-IB-01212, a Highly N-Methylated Cyclic Peptide

“…ESNA-A009 . The compound shows micromolar activity in various tumor cell lines, including LNCaP (prostate cancer), SK-BR-3 (breast cancer), HT-29 (colon cancer), and HELA (cervical cancer) . Like thiocoraline, an antitumor cyclothiodepsipeptide belonging to the same chemical family, IB-01212 features a C2-symmetrical structure, but rather than the heterocyclic bisintercalator chromophores of the former, it contains N , N Me 2 -Leu groups.…”

Total Solid-Phase Synthesis of Dehydroxy Fengycin Derivatives

“…In fact, the synthesis of cyclic depsipeptides, either in solution or on solid 6 phase, has only been reported for those peptides bearing an ester bond involving the ß-hydroxyl group of a Ser or a Thr residue. [30][31][32][33][34] Recently, we have established a convenient solid-phase strategy for the preparation of the macrolactone of eight amino acids present in fengycins. 35 The key steps of the synthesis were the formation of the phenyl ester bond and the on-resin head-to-side-chain cyclization.…”

“…Their strategy comprised the solid-phase preparation of the linear precursor and its enzymatic cyclization in solution. ,, The lack of suitable synthetic protocols for fengycins could be attributed to the presence of a highly labile phenyl ester function in their structure. In fact, the synthesis of cyclic depsipeptides, either in solution or on solid phase, has only been reported for those peptides bearing an ester bond involving the ß-hydroxyl group of a Ser or a Thr residue. − Recently, we established a convenient solid-phase strategy for the preparation of the macrolactone of eight amino acids present in fengycins . The key steps of the synthesis were the formation of the phenyl ester bond and the on-resin head-to-side-chain cyclization.…”