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

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

  • Bioorg Med Chem. 2022 Jan 1;53:116551. doi: 10.1016/j.bmc.2021.116551.
Rukman Muslimin 1,  Natsumi Nishiura 2,  Aiko Teshima 2,  Kiep Minh Do 3,  Takeshi Kodama 3,  Hiroyuki Morita 3,  Cody Wayne Lewis 4,  Gordon Chan 4,  Ahmed Taha Ayoub 5,  Kenji Arakawa 6
Affiliations

Affiliations

  • 1 Unit of Biotechnology, Division of Biological and Life Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
  • 2 Unit of Biotechnology, Division of Biological and Life Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8530, Japan; Hiroshima Research Center for Healthy Aging (HiHA), Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
  • 3 Institute of Natural Medicine, University of Toyama, 2630-Sugitani, Toyama 930-0194, Japan.
  • 4 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2J7, Canada.
  • 5 Medicinal Chemistry Department, Heliopolis University, 3 Cairo-Belbeis Desert Road, El-Nahda, Qism El-Salam, Cairo 11777, Egypt.
  • 6 Unit of Biotechnology, Division of Biological and Life Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8530, Japan; Hiroshima Research Center for Healthy Aging (HiHA), Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8530, Japan. Electronic address: karakawa@hiroshima-u.ac.jp.
PMID: 34883453 DOI: 10.1016/j.bmc.2021.116551
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.

Keywords

Antitumor activity; Carbocyclic polyketide; Chemoenzymatic synthesis; Computational prediction; Drug design; Pyrroloquinoline quinone-dependent dehydrogenase.

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