Total Synthesis and Biological Evaluation of Modified Ilamycin Derivatives

Abstract

Ilamycins/rufomycins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis. The cyclic peptides target the AAA+ protein ClpC1 that, together with the peptidases ClpP1/ClpP2, forms an essential ATP-driven protease. Derivatives of the ilamycins with a simplified tryptophane unit are synthesized in a straightforward manner. The ilamycin derivative 26 with a cyclic hemiaminal structure is active in the nM-range against several mycobacterial strains and shows no significant cytotoxicity. In contrast, derivative 27, with a glutamic acid at this position, is significantly less active, with MICs in the mid µM-range. Detailed investigations of the mode of action of 26 indicate that 26 deregulates ClpC1 activity and strongly enhances ClpC1-WT ATPase activity. The consequences of 26 on ClpC1 proteolytic activities were substrate-specific, suggesting dual effects of 26 on ClpC1-WT function. The positive effect relates to ClpC1-WT ATPase activation, and the negative to competition with substrates for binding to the ClpC1 NTD.

Synthesis and biological evaluation of moiramide B derivatives

“…For several years, our group has been involved in the total synthesis of natural products, 13 preferentially with anticancer 14 and antibiotic activities, 15 and we thus became interested in moiramides as well. As previous SAR studies on moiramide B and andrimid derivatives indicated, the fatty acid side chain is structurally highly variable.…”

Steglich esterification: A versatile synthetic approach toward the synthesis of natural products, their analogues/derivatives

“…Ilamycin and its derivatives were obtained from Streptomyces insulates (A-165-Z1) and were found active against Mycobacterium phlei and Mycobacterium 607 [ 25 , 26 ]. Greve et al, in 2022, proposed the total synthesis of Ilamycin and its derivatives by employing asymmetric hydrogenation, Claisen rearrangement and Steglich esterification as key steps [ 27 ]. The synthesis commenced from commercially available nitrotyrosine 5 which was converted to amino acid building block 6 over a few steps.…”

Recent Advances in Polypeptide Antibiotics Derived from Marine Microorganisms

“…Ilamycins are not active against Gram-positive or Gram-negative bacteria in general, but they have impactful anti-M. tuberculosis activity, with ilamycin J (12, Table 1) reaching a minimal inhibitory concentration (MIC) of 9.6 nM against M. tuberculosis HR37v and ilamycins E1/E2 (6/7, Table 1) having an MIC of 9.8 nM [44,45]. An SAR investigation between analogues showed that Leu with modified side chains has an important effect on the anti-TB activity, which is enhanced when the side chain is synthesized into a hexameric ring with an adjacent imino and diminished when the side chain is oxidized to form hydroxyl groups [47]. The activity of the modified portion on tryptophane (Trp) is weakened or not affected by oxidation to form hydroxyl groups, but is greatly enhanced when the alkenyl group is oxidized to an epoxy group.…”