Recent Advances in the Synthesis and Biological Applications of Nortopsentin Analogs
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REVIEW
Recent advances in the synthesis and biological applications of nortopsentin analogs Mona Monir Kamel1, Mohamed Kamal Abdel-hameid1, Hala Bakr El-Nassan1*, Eman Adel El-Khouly1 1
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt; е-mail: [email protected] Submitted December 18, 2019 Accepted after revision March 25, 2020
Published in Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(5), 499–502
The present minireview summarizes the data published during the last decade (2012–2019) on the synthesis of nortopsentin analogs and the effect of the structural modifications on the biological activity of the synthesized analogs as antitumor, antifungal, and antiviral agents. Keywords: bisindolylimidazole, indole, marine alkaloids, nortopsentin, structural modifications.
The chemical synthesis of nortopsentins A–D was first reported by Kaswasaki et al.8,9 The unique structure and biological activity of nortopsentins A–D have attracted many researchers in medicinal chemistry during the last two decades, and most of the work done focused on the modification of the core imidazole ring by other five- or six-membered rings or on the replacement of one or both indole rings.
The oceans provide a wealth of marine invertebrates that produce structurally unique bioactive metabolites such as alkaloids. The bioactive scaffolds of marine alkaloids displayed anticancer activities against human cancer cell lines. Some of the bioactive compounds are approved by FDA and are currently undergoing clinical trials.1 Among marine alkaloids, indoles are identified as an important scaffold due to various biological activities. Most indole alkaloids showed in vitro cytotoxic and antineoplastic activity against a range of tumor cells.2–5 Nortopsentins A, B, and C, having a characteristic 2,4-bis(3'-indolyl)imidazole skeleton (Fig. 1), were isolated from the deep-water marine sponge Spongosorites ruetzleri. Nortopsentins A–C and their synthetic analog D exhibit in vitro cytotoxicity against P388 leukemia cells. In addition, they display antifungal activity against Candida albicans.3,6,7
Nortopsentin analogs as anticancer agents The synthesis of a series of 2,5-bis(3-indolyl)pyrroles was reported in 2013 by Carbone et al.10 through a two-step procedure (Scheme 1). The preparation of 2,5-bis(3-indolyl)pyrroles 4 was initiated via Vilsmeier–Haack reaction of 1-methylindoles 1 with POCl3 and N,N,N',N'-tetramethylsuccinamide (2) to afford 1,4-butanediones 3. The latter were converted into the corresponding 2,5-bis(3-indolyl)pyrroles 4 via refluxing with NH4OAc and Ac2O in AcOH. All of the tested compounds showed potent cytotoxic activity on 12 cancer cell lines with IC50 values from 0.37 to 4.4 μg/ml. Two of the prepared compounds 4 (R = H, Me) exhibited concentration-dependent antitumor activity against 42 human tumor cell lines (IC50 values 1.54 and 0.67 μM, respectively). Kumar et al.11 reported a series of bis(3-indolyl)-1,3,4oxadiazoles as nortopsentin analogs.
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