A Hexacyclic, Iboga-Derived Monoterpenoid Indole with a Contracted Tetrahydroazepine C-Ring and Incorporation of an Isoxazolidine Moiety, a Seco-Corynanthean, an Aspidosperma-Aspidosperma Bisindole with Anticancer Properties, and the Absolute Configuration of the Pyridopyrimidine Indole Alkaloid, Vernavosine

Abstract

Examination of the EtOH extract of the Malayan Tabernaemontana corymbosa resulted in the isolation of three new alkaloids, viz., cononuridine (1), an unusual hexacyclic, iboga-derived, monoterpenoid indole characterized by contraction of the tetrahydroazepine C-ring and incorporation of an additional isoxazolidine ring, taberisidine (2), a seco-corynanthean alkaloid, and conofolidine (3), an Aspidosperma-Aspidosperma bisindole that showed pronounced in vitro growth inhibitory activity against an array of human cancer cell lines, including KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, HT-29, and HCT 116 cells. The structures and absolute configurations of 1 and 3 and the absolute configuration of the novel pyridopyrimidine indole alkaloid vernavosine (4) were confirmed by X-ray diffraction analysis. A reasonable biosynthesis route to cononuridine starting from an iboga precursor is presented.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

“…The most notable members of the post-iboga alkaloids are chemotherapeutic drugs (+)-vinblastine (8) 9 and (+)-vincristine (9; Figure 1) 10 which are derived by an oxidative dimerization of catharanthine and vindoline via a C16-C21 bond cleavage of the catharanthine moiety. More recently, post-iboga alkaloids with a cleaved N4-C21 bond and a ketone functionality at C19 such as (+)-voatinggine (10), 11 (+)-tabertinggine (11), 11 and (À)-cononuridine (12) 12 were isolated. Cleavage of the C3-N4 bond of the iboga scaffold contributes to further structural diversification of the postiboga alkaloids as exemplified by the isolation of 3-hydroxy-3,4-secocoronaridine (13).…”

“…21 However, the chippiine-and dippinine-type post-iboga alkaloids 22 have never succumbed to synthesis despite their structure exposure to the synthetic community for over 30 years. 23 Furthermore, a recent outburst of isolation reports of post-iboga alkaloids 11,12,14,17,[24][25][26][27][28][29] rekindled interest in this family of natural products and has been challenging the synthetic community.…”

Synthesis of novel isoxazoline and isoxazolidine derivatives: carboxylic acids and delta bicyclic lactones via the nucleophilic addition of bis(trimethylsilyl)ketene acetals to isoxazoles

“…Isoxazoline [1][2][3][4][5][6] and isoxazolidine [7][8][9][10][11] compounds represent an important class of five-membered heterocycles with contiguous nitrogen and oxygen atoms which have attracted significant attention, mainly due to their broad range of biological activities and potential application in the pharmaceutical industry. They are considered as privileged scaffolds in drug design and synthesis.…”

Basic approaches to the synthesis of pyrrolo[1,2-a]quinolines derivatives: a review

“…One of the main directions of the development of chemistry is the search for substances with high biological effect, which can become the base for the creation of new biologically active substances that would be competitive as potential medicines in the market of imported and domestic products. Nitrogencontaining heterocyclic compounds are known as natural and synthetic molecules [1,2] that exhibit a wide range of biological effects [3][4][5]. Among various N-heterocycles, pyrrolo[1,2-a]quinoline derivatives attract considerable attention due to their unique biological activity [6][7][8][9][10][11][12].…”