Naslov
Synthesis of O- and N-harmirines, Novel Harmine-Coumarin Hybrids

Autori
Pavić, Kristina ; Poje, Goran ; Rajić, Zrinka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
EFMC-ISMC International Syposium on Medicinal Chemistry Virtual Event Book of Abstracts / - , 2021, 289-289

Skup
EFMC-ISMC International Syposium on Medicinal Chemistry

Mjesto i datum
Online, 29.08.2021. - 02.09.2021

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
harmine ; coumarin ; hybrids

Sažetak
Coumarin and harmine, naturally occurring compounds, and their derivatives exhibit a wide range of biological activities, such as anticancer, antibacterial, antimalarial, or antifungal [1, 2]. Numerous papers show that coumarins exert their anticancer activity through different pathways (cell cycle arrest, inhibition of kinases, aromatase, Hsp90, telomerase, and angiogenesis) [1]. Moreover, harmine, as well as other β-carboline alkaloids, also interact with different anticancer drug targets, such as DNA (intercalation, groove binding), topoisomerase, kinases, tubulin, etc. [2]. Thus, hybridization of coumarin and harmine could be a promising strategy to improve their activity, reduce side effects, and overcome drug resistance. To this end, we have prepared harmirines, new hybrid molecules comprising both motifs, linked by a 1, 2, 3-triazole spacer. The title compounds were obtained by applying the standard Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). To prepare harmirines, we synthesized coumarin-based azides 2a-d and harmine-based terminal alkynes 3-5. Azides 2a-d were prepared in a two-step procedure from 4-hydroxycoumarins. The first step included chlorination of coumarins with phosphorus oxychloride. The obtained coumarin chlorides 1a-d were subsequently transformed to azides 2a-d using sodium azide. The preparation of harmine-based terminal alkynes 3-5 at positions 6, 7, and 9 of the β-carboline core was previously described [4, 5]. Synthesized azides and alkynes were the starting compounds for the CuAAC reactions that resulted in three types of hybrids: 6- and 7-substituted O-harmirines 6a-d and 7a-d, respectively, and 9-substituted N-harmirines 8a-d. ‘Click’ reactions proceeded using Cu(II)-acetate precatalyst in methanol. The scheme outlines the general route leading to the title compounds. The structures of newly prepared compounds 6-8 were confirmed by standard methods (IR, 1H, 13C NMR, MS). The evaluation of their antiproliferative activity is in progress.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

POVEZANOST RADA