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Evaluation of Angularly Condensed Diquinothiazines As Potential

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Evaluation of Angularly Condensed Diquinothiazines As Potential Bioorganic Chemistry 87 (2019) 810–820 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Evaluation of angularly condensed diquinothiazines as potential anticancer T agents ⁎ Małgorzata Jeleńa, Krystian Plutaa, , Małgorzata Latochab, Beata Morak-Młodawskaa, Kinga Suwińskac,d, Dariusz Kuśmierzb a The Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, Jagiellońska 4, 41-200 Sosnowiec, Poland b The Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine, Department of Cell Biology, Jedności 8, 41-200 Sosnowiec, Poland c Faculty of Mathematics and Natural Sciences, Cardinal Stefan Wyszyński University, K. Wóycickiego 1/3, 01-938 Warszawa, Poland d A.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlevskaya ul. 18, Kazan 420008, Russia ARTICLE INFO ABSTRACT Keywords: We present efficient synthesis of isomeric types of angularly fused diquinothiazines in the reactions of2,2′- Phenothiazines dichloro-3,3′-diquinolinyl disulfide and diquinodithiin with 3-, 5-, 6- and 8-aminoquinolines. The pentacyclic Azaphenothiazines diquinothiazine ring systems were identified as diquino[3,2-b;3′,4′-e][1,4]thiazine, diquino[3,2-b;5′,6′-e][1,4] Thiazine ring formation thiazine, diquino[3,2-b;6′,5′-e][1,4]thiazine and diquino[3,2-b;8′,7′-e][1,4]thiazine with advanced two-dimen- Anti-proliferative activity sional 1H and 13C NMR techniques (COSY, ROESY, HSQC and HMBC) of N-methyl derivatives. The identification Gene expression analysis of pentacyclic ring system was confirmed by X-ray diffraction analysis of selected N-alkyl derivatives. The X-ray 2D NMR correlation X-ray analysis analysis revealed different spatial structures of the ring system (planar and folded). NH-diquinothiazines were further transformed into N-alkyl and N-dialkylaminoalkyl derivatives. Most of diquinothiazines exhibited sig- nificant cancer cell growth inhibition against the human glioblastoma SNB-19, colorectal carcinoma Caco-2, breast cancer MDA-MB-231 and lung cancer A549 cell lines with the IC50 values < 3 µM. This anti-proliferative activity was found to be more than for cisplatin. The most promising compound, 7-dimethylaminopropyldiquino [3,2-b;6′,5′-e]thiazine, was used for gene expression analysis by reverse transcription–quantitative real-time PCR (RT–QPCR) method. The expression of H3, TP53, CDKN1A, BCL-2 and BAX genes revealed that this compound inhibited the proliferation in all cells (H3) and activated mitochondrial events of apoptosis (BAX/BCL-2) in two cancer cell lines (SNB-19 and Caco-2). 1. Introduction novel scaffolds in medicinal chemistry [6,7]. One of the most bioactive heterocyclic rings is a 6-membered 1,4-thiazine ring, containing the Cancer is a major public health problem all over the world and one nitrogen and sulfur atoms [8]. When this ring is condensed with two of the leading causes of death worldwide affecting millions of people benzene rings on both sides, it forms a tricyclic dibenzothiazine ring every year. The main forms of a curative treatment for tumors are system called phenothiazine. Compounds with this system possessing surgery, radiation, chemotherapy, hormone therapy, immune therapy, the dialkylaminoalkyl groups at the nitrogen atom (and additional and targeted therapy. The goal of current chemotherapy is to cure the simple group at the carbon atom in position 2) are also called phe- tumor, to prolong survival and to reduce the tumor burden to alleviate nothiazines and are recognized for 5 decades as the neuroleptic, anti- symptoms. A lot of effort has been applied to the synthesis ofnew histaminic, antitussive and antiemetic drugs [9]. chemotherapeutic agents/potential anticancer drugs with better se- Antipsychotic phenothiazines are low toxic, inexpensive and rela- lectivity and minor side effects but the results still do not meet ex- tively easy to obtain. They have been used as good targets for drug pectations [1–5]. repurposing [5]. Thioridazine, one of the most known phenothiazines, Bioactive heterocyclic compounds of natural and synthetic origin exhibits significant properties for multidrug-resistant tuberculosis, contain various heterocyclic ring systems (differing in the ring size and methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-re- the kind of heteroatoms) play an important role for the development of sistant enterococci [5,10–12] and lung cancer therapy through ⁎ Corresponding author at: The Medical University of Silesia, Department of Organic Chemistry, Jagiellońska 4, 41-200 Sosnowiec, Poland. E-mail address: [email protected] (K. Pluta). https://doi.org/10.1016/j.bioorg.2019.04.005 Received 30 January 2019; Received in revised form 28 March 2019; Accepted 5 April 2019 Available online 06 April 2019 0045-2068/ © 2019 Elsevier Inc. All rights reserved. M. Jeleń, et al. Bioorganic Chemistry 87 (2019) 810–820 targeting lung cancer stem cells, and is both efficient and safe [13]. dialkylaminoalkyl substituents at the thiazine nitrogen atom, their The other way to explore the phenothiazine scaffold is a modifica- structural analysis, and the evaluation of their anti-proliferative activity tion of its structure towards novel phenothiazines with new bioactivity. against cancer cells. It can be achieved mainly by introduction of new substituents at the thiazine nitrogen atom (many intermediates are commercially available 2. Results and discussion as 10H-phenothiazines) and by replacement of one or two benzene rings with various azine rings (to form varied azaphenothiazines). 2.1. Synthesis Numerous original reports, reviews and chapters in monographs de- scribe new promising biological activity of modified phenothiazines For the synthesis of new diquinothiazines, 2,2′-dichloro-3,3′-diqui- such as anticancer, antiviral, anti-inflammatory, immunosupressive, nolinyl disulfide 3 and diquinodithiin 4 (Scheme 1) were used as antibacterial, and reversal of multi-drug resistance [14–19]. They are starting materials. Those compounds reacted with 3-, 5-, 6- and 8- promising candidates for further studies in the treatment of Creutzfeldt- aminoquinolines in boiling monomethyl ether of diethylene glycol (a Jakob’s, Alzheimer’s, Parkinson’s and Huntington’s diseases [20,21]. very effective solvent, high boiling and miscible with water [33]) or The quinoline scaffold is prevalent in a variety of pharmacologically with their hydrochlorides (without a solvent) at 200–205 °C. In the case active synthetic and natural compounds [22]. Quinoline compounds of diquinodithiin 4, the reaction runs as the thiazine ring opening at the have been known for almost 400 years as alkaloids of antimalarial ac- 2-quinolinyl carbon atom (in position 4a and 5a) which is susceptible tivity (quinine, quinidine) [23]. Synthetical quinoline derivatives based for nucleophilic substitution. Both substrates lead to diquinolinyl on the aminoquinoline moiety (chloroquine, amodiaquine, primaquine) amines 5, 8, 10 and 13 (not isolated) which cyclized to NH-diqui- are recognized antimalarial drugs [22,24]. Fluoroquinolones (cipro- nothiazines 6H or/and 7H, 9H, 11H or/and 12H and 14H depending floxacine and ofloxacine) are one of the most promising and widely on the direction of the thiazine ring closure. Only one product was used in contemporary anti-infective chemotherapy [25,26]. Other qui- observed in each case. The reactions of disulfide 3 were more effective noline compounds exhibit anticancer, antimycobacterial, antic- than those of dithiin 4. The microwave-assisted synthesis using dis- onvulsant, anti-inflammatory, cardiovascular and antileishmanial ac- ulfide 3 shortened the reaction time from 3 h (for classical synthesis) to tivities [24]. Recent studies have shown that quinoline compounds 0.5 h giving NH-diquinothiazines with better yield (from a few to over a derived from substitution of the quinoline ring and fusion this ring with dozen percent). other heterocyclic rings display potent anticancer activity targeting After the structure analysis, NH-diquinothiazines were further different sites like topoisomerase I, telomerase, farnesyl transferase, transformed into N-substituted derivatives (6a-i, 9a, 11a-h and 14a-g), tyrosine kinase, tubulin polymerization and protein kinase CK-II possessing the methyl, allyl, propynyl and varied dialkylaminoalkyl [24,27]. groups in the reactions with appropriate alkyl halides in various con- One type of modified phenothiazines are azaphenothiazines, where ditions (Scheme 2). In the case of 14H-diquinothiazine 9H an in- the thiazine ring is fused with an azine ring. The fusion with one or two troduction of other groups than the methyl was unsuccessful, probably quinoline moiety instead of the benzene rings leads to the formation of due to steric hindrance. The choice of those substituents was dictated quinobenzothiazines and diquinothiazines. Selected substituted quino- by spectroscopic structural analysis (the methyl group) and their benzothiazines 1a-b and diquinothiazines 2a-b (Fig. 1) exhibit sig- pharmacophoric activity found in other azaphenothiazines [19,28,32]. nificant anticancer activity against tens of cancer cells derived from leukemia, melanoma, non-small cell lung, colon, CNS, ovarian, renal, prostate, breast and skin cancers [28–32]. These compounds show also 2.2. Spectroscopic structural analysis promising antioxidant activity on rat hepatic microsomal membranes for protection of non-enzymatic lipid peroxidation
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