Department of Chemistry, Faculty and Graduate School of Science, Kyushu University , 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
Graduate School of Agricultural Science, Tohoku University , 1-1 Tsutsumidori Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan.
J Org Chem. 2017 Sep 15;82(18):9595-9618. doi: 10.1021/acs.joc.7b01658. Epub 2017 Sep 6.
Structure-activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki-Hiyama-Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18% inhibition, respectively, at 300 μM, whereas the NOPQR(S) ring system elicited no inhibitory activity.
结构-活性关系研究的鳗毒素 (MTX)，海洋天然产物产生的一个附生甲藻，用化学合成的模型化合物进行了相应的部分结构的 MTX。两种对映体的 LMNO 环系统合成醛的 LM 环和酮的 NO 环通过 aldol 反应。这些片段是从一个共同的顺式融合吡喃吡喃中间体通过涉及序列制备诺扎基 - 希亚马 - 基希反应、分子内氧杂迈克尔加成和 Pummerer 重排。NOPQR(S)环系统，其中原始的七元 S 环被取代与一个六元环，也合成的 QR(S)环炔烃和 NO 环醛和通过 1,4-还原、脱水、硼氢化构建的 P 环。合成标本对 MTX 诱导的 Ca 内流的抑制活性进行了评价。LMNO 环系统及其对映体诱导 36 和 18%的抑制率，分别在 300 μM，而 NOPQR(S)环系统没有抑制活性。
