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  2. 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.
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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