Structure-activity relationship study of new carbazole sulfonamide derivatives as anticancer agents with dual-target mechanism

Cancer is one of the most common diseases afflicting human beings, and one in 5 people worldwide develop cancer during their lifetime according to the estimation of the International Agency for Research on Cancer (IARC) [1]. Chemotherapy is one of most effective therapies for cancer treatment [2]. Microtubule-targeting agents (MTAs) such as paclitaxel and vinblastine binding to the taxane- or vinca alkaloid-binding sites in tubulins have been successfully used as active antineoplastic agents against numerous types of cancer, including breast cancer, lung cancer, and ovarian cancer. However, their therapeutic efficacy is limited by multidrug resistance, dose-dependent toxicities, and undesirable side effects [[3], [4], [5]]. Recently, many small molecule colchicine-binding site inhibitors (CBSIs) have received increasing attention due to their potent anticancer effects against multidrug resistance of cancer cells. Some compounds have entered clinical trials for the treatment of various cancers (Fig. 1) [[6], [7], [8], [9], [10], [11]]. For example, CA-4P (Fosbretabulin, a water-soluble sodium phosphate prodrug of CA-4) was in Phase II/III clinical trials for the platinum-resistant ovarian cancers (Clinical Trials. govIdentifier: NCT02641639) [6,7]. Compounds A and B were capable of overcoming the overexpression of ABC transporters-medicated multi-drug resistance or paclitaxel-resistance in A375/TXR and PC-3/TXR respectively [9,10]. Additionally, these compounds were capable of inhibiting cell invasion and metastasis [10,11]. Some CBSIs also exert a unique vascular-disrupting effect in solid tumors, which is considered one of the best characteristic that clinical chemotherapy drugs can have [12]. Thus, CBSIs are considered to have great advantages as the next-generation MTAs. However, the potential clinical applications of many CBSIs have so far been halted by the limited therapeutic indices, the low solubility, or the low bioavailibility [7,11,12]. Therefore, the discovery of novel CBSIs with improved therapeutic indices and safety profiles is still of great value to cancer therapy.

In recent years, compounds containing carbazole moiety have been widely developed as novel anticancer candidates [13,14]. These carbazole derivatives with the similar structure displayed a high molecularly targeted selectivity and less toxic side effects (Fig. 2) [[15], [16], [17], [18], [19], [20]]. Celiptium and alectinib, two carbazole derivatives, were used in the treatment of metastatic breast cancer and adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) acted as topoisomerase II inhibitors, respectively [14]. Compound D acted as a topo II inhibitor was found to display higher cancer cell selectivity index (SI) than that of ellipticine (MCF-10A/MCF-7: SI = 76 vs. SI = 1) [15]. Compound E was found to target STAT3 phosphorylation and used in the treatment of triple-negative breast cancer and cancer with constitutive STAT3 signaling [16]. Compound F, a RORγt agonist, was studied as a potential small molecule therapeutics for cancer immunotherapy [17].

We developed a series of structurally novel carbazole sulfonamide as antimitotic agents, among them, 2,6-dimethoxypyridine substituted carbazole sulfonamide IMB105 showed a potent activity in drug-resistant SMMC-7721 hepatoma cell and MCF-7/Dox/P-gp cell at nanomolar levels [[18], [19], [20]]. Introduction of 7-NH2 and 7-OH in the carbazole ring of IMB105 not only significantly improved the cytotoxicity against panel of cancer cell lines but also improved the aqueous solubility. Compounds 1 and 11 demonstrated robust antiproliferative activities against HepG2 (hepatoma cancer), MCF-7 (breast cancer), and MIA PaCa-2 (pancreatic cancer) cells with IC50 values of 12–92 nM [21]. Compound 11 significantly inhibited tumor growth in the human ESCC (esophageal squamous cell carcinoma) xenograftmouse model in vivo [22]. The sodium phosphate prodrug of 11 displayed more potent against inhibiting tumor growth of human HepG2 xenograft than that of CA-4P [23].

In the structure-activity relationship studies for combretastatin analogues, 3,4,5-trimethoxyphenyl substituents was considered to be essential for good biological activities as shown in Fig. 1. 3,4,5-trimethoxyphenyl substituted carbazole sulfonamide showed more antiproliferative activity against MCF-7 cells in vitro than that of IMB105 (EC50: 89 nM vs. 241 nM) [19], but exhibited the same antitumor activity in human MCF-7 xenograft mice models in vivo (100 mg/kg, i. p., p2d: IR 75 % vs. 76 %), which hints a favorable bioavailability of IMB105 in vivo [18,20]. Therefore, based on the 7-NH2 and 7-OH carbazole moiety, further research was needed to better understand the influence of various substitutions on the B-ring against antitumor activity and establish drug candidates for cancer therapy. In this paper, we found that compounds 7 and 15 with 4-chloro-2,5-dimethoxy substitution exhibited remarkable antiproliferative activity (Fig. 2). Herein, we report the optimization of prodrug derivatives of compound 1, the influence of various substitutions on the B-ring in this new class of compounds and the mechanism studies, and the evaluation of their antitumor efficacy.

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