Total synthesis and biological activity of dolastatin 16

Abstract

The total synthesis of dolastatin 16, a macrocyclic depsipeptide first isolated from the sea hare Dolabella auricularia as a potential antineoplastic metabolite by Pettit et al., was achieved in a convergent manner. Dolastatin 16 was reported by Tan to exhibit strong antifouling activity, and thus shows promise for inhibiting the attachment of marine benthic organisms such as Amphibalanus amphitrite to ships and submerged artificial structures. Therefore, dolastatin 16 is a potential compound for a new, environmentally friendly antifouling material to replace banned tributyltin-based antifouling paints. The synthesis of dolastatin 16 involved the use of prolinol to prevent formation of a diketopiperazine composed of L-proline and N-methyl-D-valine during peptide coupling. This strategy for the elongation of peptide chains allowed the efficient and scalable synthesis of one segment, which was subsequently coupled with a second segment and cyclized to form the macrocyclic framework of dolastatin 16. The synthetic dolastatin 16 exhibited potent antifouling activity similar to that of natural dolastatin 16 toward cypris larvae of Amphibalanus amphitrite.

Marine natural products

“…Total synthesis of dolastatin 16 has been reported, and its potent antifouling activity towards barnacle cyprids conrmed. 632 Three studies reported on new biologically active analogues of the dolastatin 10 peptide scaffold. [633][634][635] Novel tambjamine analogues have been shown to activate the p38 MAPK pathway leading to in vitro and in vivo activity towards lung cancer cell lines.…”

Residual Complexity Does Impact Organic Chemistry and Drug Discovery: The Case of Rufomyazine and Rufomycin

“…The loss of activity was attributed to either an unidentifiable contaminat or a solvent-induced conformational change associated with the synthetic compound. On a more encouraging note, the Matsuda group synthesized dolastatin-16 and found it to be a potent antifouling agent against Amphibalanus amphitrite , 29 suggesting that a lack of cancer cell inhibition may not be the end of the development prospects of dolastatin-16.…”

Mini-Review: Antifouling Natural Products from Marine Microorganisms and Their Synthetic Analogs

“…More encouragingly, field testing of dolastatin 16 was conducted at concentrations of 10.0, 1.0, 0.1, and 0.01 μg/mL, respectively, and the barnacle counts of all dolastatin 16-treated plates were obviously lower than that of the negative controls after 4 weeks, suggesting its potential application as an antifoulant [ 58 ]. Although its total synthesis was challenging due to its complex structure, dolastatin 16 has been recently successfully synthesized by Casalme et al [ 59 ]. The synthetic dolastatin 16 showed potent antilarval settlement of B. amphitrite similar to that of natural dolastatin 16, which further supported that dolastatin 16 might be explored as a candidate antifoulant.…”