5,6-Dihydropyrrolo[2,1-<i>a</i>]isoquinolines as Alternative of New Drugs with Cytotoxic Activity

Abstract

In this study, the pyrrolo[2,1-a] isoquinolines 4a-n were synthesized in good yields in a three steps synthesis from the corresponding α,β-unsaturated esters starting materials. These compounds were tested on six human cancer cells lines to measure the cytotoxic activity as a function of the electronic properties and aromaticity of the substituent at the C-2 position of the pyrroloisoquinoline. Our results reveal that the cytotoxic activity could be explained in terms of the distribution of electronic density across the ring joined to C-2. Also, this study identified 3-hydroxy (4d) and 3-chloro (4j) derivatives with powerful cytotoxic activities. The IC 50 values of these compounds were found to be comparable to those of the commercially available Topotecan, Irinotecan, Etoposide, Tamoxifen, and Cisplatin.Key words pyrrolo[2,1-a]isoquinoline; synthesis; cytotoxic activity Cancer is a leading cause of death worldwide, and according to the World Cancer Research Fund International (GLOBOCAN 2012), an estimated 17.1 million new cancer cases and 10.0 million cancer-related deaths will occur in 2020, compared with 15.2 million and 8.9 million, respectively, in 2015.1) The most commonly diagnosed cancers worldwide are cancers of the skin (melanoma), prostate, lung, breast, and colorectum.2) Cancer poses a challenge to researchers searching for potent drugs that are capable of controlling cancer growth while minimizing side effects or the development of drug resistance. Our group is currently engaged in a program aimed at synthesizing novel heterocyclic compounds that inhibit the growth of cancer cells. We recently synthesized the pyrroloisoquinolines I-IV 3,4) ( Table 1) in a threestep protocol, and their cytotoxic activities were tested on six tumor cell lines: PC-3 (human prostatic adenocarcinoma), U-251 (human glioblastoma), K-562 (human chronic myelogenous leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), and SKLU-1 (human lung adenocarcinoma). The results of this study (Table 1), allowed us to establish preliminary structure-activity relationship (Fig. 1) that revealed the importance of the aromatic substituent at the C-2 position, particularly when the substituent was a m-(cyclohexylmethylpiperazinamide)phenyl (I), phenyl (II), or m-(amino) phenyl (III), substituent, in combination with an ethyl ester at the C-1 position. Following up on these preliminary structure-activity studies, the present work sought to synthesize the novel pyrroloisoquinolines 4a-c (Fig. 2) to evaluate the effects of modifying the cyclohexylmethylpiperazinyl moiety on the antiproliferative activity. Compounds 4d-k (Fig. 2) were evaluated to determine the role of the phenyl ring substituent on the antiproliferative activity of the compound. Compounds 4l-n (Fig. 2) were evaluated to determine the effect of modifying the aromaticity of the C-2 substituent on the antiproliferative activity. Results and DiscussionChemistry The synthetic route to compounds 4a-n is depicted in Chart 1. Compounds 4a-n wer...

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