Molinski Tadeusz F
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0358, United States.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0358, United States.
J Nat Prod. 2025 Jan 24;88(1):205-210. doi: 10.1021/acs.jnatprod.4c01295. Epub 2024 Dec 20.
Marine sponge diterpenoid isonitriles are exceptional nitrogenous natural products that exhibit antiplasmodial activity. Their biosynthesis presents a biosynthetic puzzle: how do the elements of NC engage terpenyl carbocations in isoprenoid secondary metabolism, and what is the biosynthetic precursor of the NC group? Cyanoformic acid (NC-COOH, ) is proposed as a plausible delivery vehicle of NC that resolves a paradox in the commonly held proposition that an inorganic cyanide anion, CN, terminates terpenoid isonitrile (TI) biosynthesis. DFT calculations of NC-COOH and its conjugate base, cyanoformate, NC-COO (), support high nucleophilicity at N and explain bond-forming constitutionality: attack at N and formation of an isonitrile over its nitrile isomer. TI biogenesis is compared to the cyanoformamide-containing ceratamines that arise from oxidation of a terminal -Gly amide precursor. A unifying model links C-NC vs C-CN bond formation and places Gly at the center of both biosynthetic schemes.
海洋海绵二萜异腈是一类具有抗疟活性的特殊含氮天然产物。它们的生物合成存在一个谜题：在类异戊二烯次级代谢中，NC基团的元素是如何与萜基碳正离子结合的，以及NC基团的生物合成前体是什么？氰基甲酸（NC-COOH）被认为是一种合理的NC传递载体，它解决了一个普遍观点中的矛盾，即无机氰化物阴离子CN会终止萜类异腈（TI）的生物合成。对NC-COOH及其共轭碱氰基甲酸酯（NC-COO）的密度泛函理论计算支持了N处的高亲核性，并解释了成键的合理性：在N处进攻并形成异腈而非其腈异构体。将TI生物合成与由末端-Gly酰胺前体氧化产生的含氰基甲酰胺的角胺进行了比较。一个统一的模型将C-NC与C-CN键的形成联系起来，并将Gly置于两种生物合成途径的中心。
