期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 53, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116551
关键词
Carbocyclic polyketide; Antitumor activity; Pyrroloquinoline quinone-dependent dehydro- genase; Chemoenzymatic synthesis; Computational prediction; Drug design
资金
- JSPS-MOSR/STDF Bilateral Joint Program (JSPS, the Japan Society for the Promotion of Science
- MOSR/STDF, Ministry of Scientific Research/Science and Technology Development Fund)
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) [23108515, 25108718, 17H05446]
- JSPS [16H04917]
- JSPS A3 Foresight Program
- Izaak Walton Killam Memorial Scholarship
- NSERC Discovery Grant [RGPIN-2016-06466]
- Canadian Institutes of Health Research Project Grant [PJT-159585]
- Indonesia Endowment Fund for Education (LPDP)
- Grants-in-Aid for Scientific Research [17H05446, 16H04917, 25108718] Funding Source: KAKEN
In this study, the importance of the 8-lactone ring in lankacidin C was investigated. The results showed that the 8-lactone moiety has minimal impact on the antitumor activity of lankacidin-group antibiotics.
We investigated the importance of the 8-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 8-lactone moiety. Orf23 could convert the mono cyclic 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 8-lactone moiety is less important for antitumor activity in lankacidin-group antibiotics.
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