Design, Synthesis and Bio-Evaluation of New Phenothiazine Derivatives of Sulfonamide Dyes As Anticancer Agents
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RESEARCH ARTICLE 1G.H. Raisoni College of Engineering, Nagpur, Maharashtra 440016, India 2Department of Chemistry, RTM Nagpur University, Nagpur, Maharashtra 440033, India 3Rajiv Gandhi College of Engineering & Research, Nagpur, Maharashtra 441110, India Introduction malignancy and leads to many side-effects, like pain, Cancer, the 2nd main reason of death after cardiac disease, nausea, vomiting, loss of hair and that in turn, limits the asserting more than 7 million deaths in last decade, the efficacy of the attempted therapy. Recently, an most current global statistics for cancer [1]. As compared apprehensive research has been carried out for the finding to men women are prone to more types of cancer [2,3]. In and developing novel selective anti-cancer agents, which the year 2030 12 million deaths is expected as the death are devoid of number of the terrible side effects of regular from cancer worldwide are likely to keep on growing. anti-cancer agents [9]. A broadly used anti-psychotic Whereas the principal means of cancer treatment are drugs that chiefly act on central dopamine receptors and surgery, radiation, and chemotherapy, [4] the beleaguered inhibits tumour cell proliferation are drugs of chemotherapy acts on specific noticeable molecular Phenothiazine derivatives which are relatively secure. anomalies for few tumors, and which lessens destruction They show varying degree of antiemetic, sedative, anti- to normal live cells, is appealing progressively hopefully psychotic, hypothermic and analgesic effects. The drug popular [5]. chlorpromazine, a drug from the same class being studied Drug discovery-development, is a prolonged and and found that it can enhance the cytotoxic effects of expensive procedure and so, computational methods are tamoxifen on breast cancer. Resistance to required for generating the lead and their optimization in chemotherapeutic drug can be reversed cisplatin, a the process of discovery-development by significantly Phenothiazine drugs by enhancing the sensitivity [10]. plummeting the phase time. The in-silico approach are Phenothiazine derivatives constitutes an important class of being paid more attention which can lead the enhancement thiazines heterocyclic ring system and possess diverse for designing novel anticancer drug after the development activities as neuroleptics tranquilizers, antimalarial, anti- of the first peptide-based HIV protease inhibitors and Parkinson, anti-convulsant, anti-histaminic, antiviral, anti- inhibitors of the H5N1 avian influenza [6]. Molecular helminthic, anticancer, antibacterial and CNS-depressant docking can be understood as an optimization test that [11]. Phenothiazines are inexpensive and widely available, illustrates the “best-fit” ligand orientation. Ligand binds to and therefore have been examined as anticancer drugs. In a specific protein and is used to deduce the assembly of search for better active moieties a slight variation in the intermolecular complex formed with minimum nucleus makes a striking difference in the bioactivity [12]. binding energy for predicting affinity and activity. Recent reports on anti-cancer agents, on structurally Generating drug-receptor interactions through molecular novel sulfonamide derivatives found to show substantial docking studies can be taken as a modern drug designing, antitumor activity in vitro and/or in vivo [13]. The process [7]. In chemotherapy for cancer the major focus of sulfonamide antimicrobial drugs were the first effective research includes the discovery, characterization and chemotherapeutic agents but the rapid development of development of novel and safe cancer chemo widespread resistance diminished the usefulness of representative agents [8]. In cancer therapy cytotoxicity sulfonamides. An evaluation of azo dyes was done and and geno-toxicity of anticancer drugs to the healthy cells prontosil was found to protect against and cure are foremost problems and may induce secondary streptococcal infections in mice. The structure-activity study on the sulfonamide azo dyes was performed and the Advanced Materials Proceedings reductive cleavage of azo linkage to release the active looking to their environmental incompatibility, [23,24] antibacterial product, sulfonamide, was concluded. silica sulfuric acid (SiO2-O-SO3H), a environmentally Further, sulphonamide containing compounds have benign solid acid, was used [25]. enormous potential as pharmaceutical and agricultural Considering the above findings about importance of agents, due to their diverse biological profile. They have phenothiazine and sulfonamide derivatives as anti-cancer extensively been documented for their wide variety of agent, we designed novel phenothiazine derivatives pharmacological activities such as antimicrobial, insulin containing sulfonamide moiety as three different anti- releasing, anti-diabetic, diuretic, anti-carbonic anhydrase, cancer target enzyme inhibitors viz. topoisomerase-II, anti-thyroid, anti HIV and anti-tumour activity among aromatase and CDK2. Due to the presence of a polar others. Already it has been exploited clinically for treating pocket in the active site of aromatase enzyme, the a variety of diseases like epilepsy, glaucoma, congestive hydrophilic sulfonamide group was connected to the heart failure, gastric, mountain sickness, and duodenal phenothiazine scaffold as a proton acceptor or donor to ulcers or as diuretic agents, but a little explored as combine their positive effects. In this study, we tried antitumor drugs [14]. Current advances in bio-medical describing the designing via docking study, synthesis and sciences and combinatorial chemistry have lead to the evaluation of4-(4-((10H-phenothiazin-10-yl) sulfonyl) design and synthesis of hundreds of new anti-neoplastic phenyl) diazenyl derivatives 5a-g as anti-cancer agents. agents and by understanding the drug action we can ration ally design newer drugs with selectivity and reduced side Results and discussion effects. However, the exact biology of cancer still remains Modeling of the three enzymes (topoisomerase II, angiomatous at large, offering a lot of scope for the aromatase and CDK2) and ligands research targeting the malignant cells [15]. The combination of two or more pharmacophores in a single On precise analysis of the active site of all the three molecule is one of the major approaches for designing of enzyme is recapitulated according to docking dataset. The new biologically active moiety. Structural fragments with active site of Aromatase is contemplated to be Ala438, heterocyclic moieties are most obvious among all drugs Arg115, Arg145, Ilu132, Ilu152, Ilu372, Ilu477, Gly439, [16]. Met311, Thr310, Try224, Val370 and other amino acids Estrogen receptor-positive cases of breast cancer around in the site. The residues contributing to the accounting around 70% of the total cases, contains catalytic cleft of CDK2 are Ala31, Ala144, Asp86, Gln85, receptors that attach to the estrogen hormone [17]. His84, Ilu10, Leu134, Lys89, Phe80, Val18, etc. The Estrogen levels are lowered by aromatase inhibition. active site of Topoisomerase II is considered to be Arg81, These drugs lower estrogen levels in females whose Asn51, Glu55, Ile48, Ile98, Met83, Pro84, Thr94, Val76, ovaries aren’t making estrogen (say a women with Val174, etc. menopause) [18]. The quick evaluation of binding energies for Recent evidence suggests that Cycline Dependent topoisomerase II, aromatase and CDK2, structure-based Kinase 2 (CDK2) seems to have a essential role in the G2 drug design: molecular docking studies was carried out. phase of the cell cycle progression that has led to an active First, we examined all the designed phenothiazine pursuit of small molecule inhibitors of this enzyme may be derivatives of sulfonamide dyes (5a-5g) with three helpful in treatment against cancer and other hyper- anticancer drug target enzymes (topoisomerase II, proliferative disorders [19]. aromatase and CDK2). The the ligand binding affinities The physiological function of Topoisomerase II is was estimated as energy score (kcal/mol). The compounds explained in mechanistic detail elsewhere [20]. displaying the maximum binding affinity, least dock score, In concurrence with our efforts to develop broad is the one forming the most stable ligand-enzyme spectrum phenothiazine derivatives of sulfonamide dyes complex. The binding models were assessed from the as anticancer agents that are based on the analysis of the number of hydrogen bonds. As shown in Table 1 all the interaction of the anticancer drug target enzymes designed ligands showed better dock score with aromatase (topoisomerase II, aromatase and CDK2) with the enzyme as compare to topoisomerase-II and CDK2. But designed ligands, using ArgusLab 4.0. In order to (i) the dock score of almost all ligands with topoisomerase II mock-up the binding interaction between a series of and CDK2 were found to be better as compared to phenothiazine derivatives of sulfonamide dyes and the doxorubicin, a known topoisomerase II inhibitor and three enzymes, and (ii) evaluate the effects of structural flavopiridol, a known CDK2 inhibitor respectively. variation of phenothiazine derivatives of sulfonamide The amino acid residues at the active site of dyes. Various phenothiazine derivatives of sulfonamide aromatase forms two H-bond with the -SO2-and –OH dyes in which the R-groups were changed (Table 1), were group of 5a, particularly with the catalytic amino acid docked in silico, onto the three anticancer drug target Gly439 and Arg115 respectively. But