Synthesis and In Vitro Antiproliferative Activity of Amido and Amino Analogues of the Marine Alkaloid Isogranulatimide

Abstract

Marine organisms have proven to be a promising source of new compounds with activity against tumor cell lines. Granulatimide and isogranulatimide are marine alkaloids that have been shown to inhibit checkpoint kinase 1 (Chk1), a key protein in the DNA damage response and an emerging target for anticancer therapeutics. Here, we describe the synthesis and preliminary evaluation of amido and amino analogues of isogranulatimide. The new derivatives were prepared in three steps from 2-imidazol-1-yl-1H-indol-5-ylamine. Two of the compounds synthesized exhibited more potent in vitro antiproliferative activity (single-digit micromolar concentration range), by at least one log of magnitude, than the natural product isogranulatimide when evaluated in six human tumor cell lines: non-small-cell lung cancer (A549), colon cancer (LoVo), breast cancer (MCF7), oligodendroglioma (Hs683), glioblastoma (U373), and melanoma (SKMEL28). The mechanism of action of these derivatives remains to be elucidated, given that they did not significantly inhibit Chk1, however these compounds are easily synthesized and exhibit potent anticancer activity and are thus worthy of further study.

Marine natural products

“…These biomarkers, associated with epithelial-derived cell lines and also some colorectal, breast and lung cell lines, could be of use in predicting the likelihood of patient response to didemnin B or analogues in a therapeutic setting. Synthetic analogues related to the polyandrocarpamines 955 were found to be inhibitors of H 2 S production by cystathionine beta-synthase, 956 and SAR studies have been reported for thiaplidiaquinones A and B 957 (various biological targets), 958 cadiolides A-C 959,960 (antibacterial), 961,962 rubrolides 963 (photosynthesis inhibitors), 964 meridianins 965 (antimalarial and antituberculosis), 966 isogranulatimide 967 (cytotoxicity), 968 and lamellarins 969 (cytotoxicity). 970…”

Ascidian Toxins with Potential for Drug Development

“…A molecular docking based study was used to design potential new specific Chk1 inhibitors [ 161 ]. The same group also synthesized new amino or amido substituted analogs based on the granulatimide/isogranulatimide framework and examined their biological activity [ 162 ]. Two of the new compounds (where ring C is opened) were more potent than the parent compounds in inhibition of cell growth with IC 50 values in the low micromolar range.…”

Antitumor Effects and Related Mechanisms of Penicitrinine A, a Novel Alkaloid with a Unique Spiro Skeleton from the Marine Fungus Penicillium citrinum

“…Marine microorganisms have attracted great attention since they have developed unique metabolic and physiological capabilities that not only ensure survival in extreme habitats but also offer the potential to produce compounds with antitumor and other interesting pharmacological activities that would not be observed in terrestrial microorganisms [ 10 , 11 , 12 ]. Recently, several synthetic analogues with a promising anti-proliferative activity are reported [ 13 , 14 , 15 , 16 , 17 , 18 ].…”