Chemoenzymatic synthesis, computational investigation, and antitumor activity of monocyclic lankacidin derivatives

Rukman Muslimin, Natsumi Nishiura, Aiko Teshima, Kiep Minh Do, Takeshi Kodama, Hiroyuki Morita, Cody Wayne Lewis, Gordon Chan, Ahmed Taha Ayoub, Kenji Arakawa

Research output: Contribution to journalArticlepeer-review

Abstract

We investigated the importance of the δ-lactone ring (C1–C5) in lankacidin C using chemoenzymatic synthesis and computational prediction and assessing biological activity, including antitumor activity. Pyrroloquinoline quinone-dependent dehydrogenase (Orf23) in Streptomyces rochei was used in the chemoenzymatic synthesis of lankacyclinone C, a novel lankacidin C congener lacking the δ-lactone moiety. Orf23 could convert the monocyclic lankacidinol derivatives, lankacyclinol and 2-epi-lankacyclinol, to the C-24 keto compounds, lankacyclinone C and 2-epi-lankacyclinone C, respectively, elucidating the relaxed substrate specificity of Orf23. Computational prediction using molecular dynamics simulations and the molecular mechanics/generalized Born-surface area protocol indicated that binding energy values of all the monocyclic derivatives are very close to those of lankacidin C, which may reflect a comparable affinity to tubulin. Monocyclic lankacidin derivatives showed moderate antitumor activity when compared with bicyclic lankacidins, suggesting that the δ-lactone moiety is less important for antitumor activity in lankacidin-group antibiotics.
Original languageJapanese
JournalBioorganic and Medicinal Chemistry
Volume53
DOIs
StatePublished - 2022/01/01

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