Abstract
The continuous attempt of drug discovery and search for a potential drug molecules with promising pharmacological activities is always of immense interest. Most of those chemical compounds having active pharmacological effects contain heterocyclic nucleus or compounds. Heterocyclic compounds clutch a particular place among pharmaceutically active natural and synthetic compounds. The ability to serve both as biomimetics and reactive pharmacophores of the heterocyclic nucleus is incredible and principally contributed to their unique value as traditional key elements of many drugs. These heterocyclic nuclei offer a huge area for new lead molecules in drug discovery and for the generation of activity relationships with biological targets to enhance their pharmacological effects. In the heterocyclic nucleus, the hydrogen bond acceptors and donors arranged in a manner of a semi-rigid skeleton in heterocyclic rings and therefore can present a varied display of significant pharmacophores. Lead identification and optimization of a probable drug target can be achieved by the generation of chemically diverse heterocyclic pharmacophores with different groups or substituents. Herein, an attempt is made to review and summarize the naturally occurring carbazole containing alkaloids obtained from Murraya, Causena and Glycosmis species and their potential towards anticancer activity. Carbazole is a tricyclic heterocyclic molecule and an integral part of naturally occurring alkaloids possessing various potential biological activities such as anticancer, antimicrobial and antiviral. Due to the high binding affinity of carbazole towards nucleic acid/ receptor and mimicking their biological activity, carbazole derived alkaloids exhibit the potential cytotoxic effect.
Keywords: Carbazole, N-Heterocyclic, cytotoxic, murrayanine, glycosmis, clausemine, lead molecule.
Graphical Abstract
[1]
Zhang B, Studer A. Recent advances in the synthesis of nitrogen heterocycles via radical cascade reactions using isonitriles as radical acceptors. Chem Soc Rev 2015; 44(11): 3505-21.
[2]
Banerjee B. Recent developments on ultrasoundassisted one-pot multicomponent synthesis of biologically relevant heterocycles. Ultrason Sonochem 2017; 35: 15-35.
[3]
Kaushik NK, Kaushik N, Attri P, et al. Biomedical Importance of Indoles. Molecules 2013; 18(6): 6620.
[4]
Sharma V, Kumar P, Pathak D. Biological importance of the indole nucleus in recent years: A comprehensive review. J Heterocycl Chem 2010; 47(3): 491-502.
[5]
Gaikwad DD, Chapolikar AD, Devkate CG, et al. Synthesis of indazole motifs and their medicinal importance: An overview. Eur J Med Chem 2015; 90: 707-31.
[6]
Nevagi RJ, Dighe SN, Dighe SN. Biological and medicinal significance of benzofuran. Eur J Med Chem 2015; 97: 561-81.
[7]
Thangadurai A, Minu M, Wakode S, Agrawal S, Narasimhan B. Indazole: A medicinally important heterocyclic moiety. Med Chem Res 2012; 21(7): 1509-23.
[8]
Bräse S, Gil C, Knepper K. The recent impact of solid-phase synthesis on medicinally relevant benzoannelated nitrogen heterocycles. Bioorg Med Chem 2002; 10(8): 2415-37.
[9]
Hopkinson MN, Richter C, Schedler M, Glorius F. An overview of N-heterocyclic carbenes. Nature 2014; 510: 485.
[10]
Kaur N. Review of Microwave-Assisted Synthesis of Benzo-Fused Six-Membered N, N-Heterocycles. Synth Commun 2015; 45(3): 300-30.
[11]
Lewis JC, Bergman RG, Ellman JA. Direct functionalization of nitrogen heterocycles via Rh catalyzed C-H bond activation. Acc Chem Res 2008; 41(8): 1013-25.
[12]
Albert A. Comparative biochemistry: The second principle of selectivity.Selective Toxicity. Dordrecht: Springer 1985; pp. 118-74.
[14]
Martins P, Jesus J, Santos S, Raposo LR. RomaRodrigues C, Baptista PV, Fernandes AR. Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift towards the Use of Nanomedicine’s Tool Box. Molecules 2015; 20(9): 16852.
[15]
Parker WB. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem Rev 2009; 109(7): 2880-93.
[16]
Shaquiquzzaman M, Verma G, Marella A, et al. Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents. Eur J Med Chem 2015; 102: 487-529.
[17]
Galloway WRJD, Isidro-Llobet A, Spring DR. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun 2010; 1: 80.
[18]
Dömling A, Wang W, Wang K. Chemistry and biology of multicomponent reactions. Chem Rev 2012; 112(6): 3083-135.
[19]
Shukla PK, Verma A, Mishra P. Significance of nitrogen heterocyclic nuclei in the search of pharmacological active compounds. New Perspective in Agricultural and Human Health 2017; pp. 100-26.
[20]
Akhtar J, Khan AA, Ali Z, Haider R, Yar MS. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur J Med Chem 2017; 125: 143-89.
[21]
Patel P, Pillai J, Darji N, Patel B. Recent advance in anti-Inflammatory activity of benzothiazole derivatives 2012.
[22]
Vitaku E, Smith DT, Njardarson JT. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J Med Chem 2014; 57(24): 10257-74.
[24]
Gündisch D, Sun D. Carbazole scaffold in medicinal chemistry and natural products: A review from 2010-2015. Curr Top Med Chem 2016; 16(11): 1290-313.
[26]
Shaikh MS, Karpoormath R, Thapliyal N, et al. Current perspective of natural alkaloid carbazole and its derivatives as antitumor agents. Anticancer Agents Med Chem 2015; 15(8): 1049-65.
[27]
Routier S, Mérour J-Y, Dias N, et al. Synthesis and biological evaluation of novel phenylcarbazoles as potential anticancer agents. J Med Chem 2006; 49(2): 789-99.
[28]
Sherer C, Snape TJ. Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives. Eur J Med Chem 2015; 97: 552-60.
[29]
Caruso A, Iacopetta D, Puoci F, Rita Cappello A, Saturnino C, Stefania Sinicropi M. Carbazole derivatives: A promising scenario for breast cancer treatment. Mini Rev Med Chem 2016; 16(8): 630-43.
[30]
Gu W, Hao Y, Zhang G, Wang S-F, Miao T-T, Zhang K-P. Synthesis, in vitro antimicrobial and cytotoxic activities of new carbazole derivatives of ursolic acid. Bioorg Med Chem Lett 2015; 25(3): 554-7.
[31]
Patil R, Patil SA, Beaman KD, Patil SA. Indole molecules as inhibitors of tubulin polymerization: Potential new anticancer agents, an update (2013-2015). Future Med Chem 2016; 8(11): 1291-316.
[32]
Singh Sidhu J, Singla R. Mayank, Jaitak V. Indole Derivatives as Anticancer Agents for Breast Cancer Therapy: A Review. Anticancer Agents Med Chem 2016; 16(2)160173
[33]
Tan S-P, Ali AM, Nafiah MA, Awang K, Ahmad K. Isolation and cytotoxic investigation of new carbazole alkaloids from Murraya koenigii (Linn.). Spreng Tetrahedron 2015; 71(23): 3946-53.
[34]
Peng WW, Zheng LX, Ji CJ, Shi XG, Xiong ZH, Shangguan XC. Carbazole alkaloids isolated from the branch and leaf extracts of Clausena lansium. Chin J Nat Med 2018; 16(7): 509-12.
[35]
Bashir M, Bano A, Subhan Ijaz A, Ahmad Chaudhary B. Recent developments and biological activities of n-substituted carbazole derivatives: A review. Molecules 2015; •••: 20.
[36]
Knölker H-J, Reddy KR. Isolation and Synthesis of Biologically Active Carbazole Alkaloids. Chem Rev 2002; 102(11): 4303-428.
[37]
Anupam N, Suvra M, Avijit B, Julie B. Review on chemistry and pharmacology of Murraya koenigii Spreng (Rutaceae). J Chem Pharm 2010; 2(2): 286-99.
[38]
Nagappan T, Ramasamy P, Wahid MEA, Segaran TC, Vairappan CS. Biological activity of carbazole alkaloids and essential oil of Murraya koenigii against antibiotic resistant microbes and cancer cell lines. Molecules 2011; 16(11): 9651.
[39]
Chakraborty DP, Barman BK, Bose PK. On the constitution of murrayanine, a carbazole derivative isolated from Murraya koenigii Spreng. Tetrahedron 1965; 21(2): 681-5.
[40]
Ramsewak RS, Nair MG, Strasburg GM, DeWitt DL, Nitiss JL. Biologically active carbazole alkaloids from Murraya koenigii. J Agric Food Chem 1999; 47(2): 444-7.
[41]
Itoigawa M, Kashiwada Y, Ito C, et al. Antitumor agents. 203. carbazole alkaloid Murrayaquinone A and related synthetic carbazolequinones as cytotoxic agents. J Nat Prod 2000; 63(7): 893-7.
[42]
Uvarani C, Sankaran M, Jaivel N, Chandraprakash K, Ata A, Mohan PS. Bioactive dimeric carbazole alkaloids from Murraya koenigii. J Nat Prod 2013; 76(6): 993-1000.
[43]
Baldeyrou B, Tardy C, Bailly C, et al. Synthesis and DNA interaction of a mixed proflavinephenanthroline Tröger base. Eur J Med Chem 2002; 37(4): 315-22.
[44]
Tanious FA, Ding D, Patrick DA, Bailly C, Tidwell RR, Wilson WD. Effects of compound structure on carbazole dication−DNA complexes: Tests of the minor-groove complex models. Biochemistry 2000; 39(39): 12091-101.
[45]
Muthumani P, Venkatraman S, Ramseshu K, et al. Pharmacological studies of anticancer, anti-inflammatory activities of Murraya koenigii (Linn) Spreng in experimental animals. In Vitro 2009; 17: 18.
[47]
Agyepong N, Agyare C, Adarkwa-Yiadom M, Gbedema SY. Phytochemical investigation and antimicrobial activity of Clausena anisata (Willd), Hook. Afr J Tradit Complement Altern Med 2014; 11(3)200209
[48]
Blumenthal RD, Lew W, Reising A, et al. Anti-oxidant vitamins reduce normal tissue toxicity induced by radioimmunotherapy. Int J Cancer 2000; 86(2): 276-80.
[49]
Chakraborty A, Chowdhury BK, Bhattacharyya P. Clausenol and clausenine—two carbazole alkaloids from Clausena anisata. Phytochemistry 1995; 40(1): 295-8.
[50]
Ito C, Itoigawa M, Katsuno S, et al. Chemical constituents of Clausena excavata: Isolation and structure elucidation of novel furanone-coumarins with inhibitory effects for tumor-promotion. J Nat Prod 2000; 63(9): 1218-24.
[52]
Shen D-Y, Chan Y-Y, Hwang T-L, et al. Constituents of the roots of Clausena lansium and their potential anti-inflammatory activity. J Nat Prod 2014; 77(5): 1215-23.
[54]
Albaayit SFA, Abba Y, Rasedee A, Abdullah N. Effect of Clausena excavata Burm. f. (Rutaceae) leaf extract on wound healing and antioxidant activity in rats. Drug Des Devel Ther 2015; 9: 3507-18.
[55]
Ito C, Katsuno S, Itoigawa M, et al. New carbazole alkaloids from Clausena anisata with antitumor promoting activity. J Nat Prod 2000; 63(1): 125-8.
[56]
Taufiq-Yap YH, Peh TH, Ee GCL, et al. A new cytotoxic carbazole alkaloid from Clausena excavata. Nat Prod Res 2007; 21(9): 810-3.
[57]
Thongthoom T, Songsiang U, Phaosiri C, Yenjai C. Biological activity of chemical constituents from Clausena harmandiana. Arch Pharm Res 2010; 33(5): 675-80.
[58]
Songsiang U, Thongthoom T, Boonyarat C, Yenjai C. Claurailas A−D, Cytotoxic carbazole alkaloids from the roots of Clausena harmandiana. J Nat Prod 2011; 74(2): 208-12.
[59]
Maneerat W, Ritthiwigrom T, Cheenpracha S, et al. Bioactive carbazole alkaloids from Clausena wallichii roots. J Nat Prod 2012; 75(4): 741-6.
[60]
Yang G-Z, Wu Y, Chen Y. Alkaloids from the stems of Glycosmis pentaphylla. Helv Chim Acta 2012; 95(8): 1449-54.
[61]
Underhill AP. Current issues in Chinese neolithic archaeology. J World Prehist 1997; 11(2): 103-60.
[62]
Ito C, Itoigawa M, Sato A, et al. Chemical constituents of Glycosmis arborea: Three new carbazole alkaloids and their biological activity. J Nat Prod 2004; 67(9): 1488-91.
[63]
Wang J, Zheng Y, Efferth T, Wang R, Shen Y, Hao X. Indole and carbazole alkaloids from Glycosmis montana with weak anti-HIV and cytotoxic activities. Phytochemistry 2005; 66(6): 697-701.
[64]
Chen Y, Tang C, Wu Y, et al. Glycosmisines A and B: isolation of two new carbazole–indole-type dimeric alkaloids from Glycosmis pentaphylla and an evaluation of their antiproliferative activities. Org Biomol Chem 2015; 13(24): 6773-81.
[65]
Ito C, Itoigawa M, Aizawa K, Yoshida K, Ruangrungsi N, Furukawa H. γ-Lactone carbazoles from Clausena anisata. J Nat Prod 2009; 72(6): 1202-4.
[66]
Caruso A, Sinicropi MS, Lancelot J-C, et al. Synthesis and evaluation of cytotoxic activities of new guanidines derived from carbazoles. Bioorg Med Chem Lett 2014; 24(2): 467-72.
[68]
Knölker HJ. Occurrence, biological activity, and convergent organometallic synthesis of carbazole alkaloids.Natural Products Synthesis II. Berlin, Heidelberg: Springer 2005; pp. 115-48.
[69]
Shams-Ud-Doha KM, Akter M, Al Mahmud Z, Apu AS, Howlader MA. Antinociceptive activity of the methanol extracts of leaves of Eugenia fruticosa (Roxb.) and Glycosmis pentaphylla (Retz.) in Swiss albino mice. J Appl Pharm Sci 2012; 2(4): 99.
[70]
Zhang F-F, Gan L-L, Zhou C-H. Synthesis, antibacterial and antifungal activities of some carbazole derivatives. Bioorg Med Chem Lett 2010; 20(6): 1881-4.
[71]
Cao N, Chen Y, Ma X, et al. Bioactive carbazole and quinoline alkaloids from Clausena dunniana. Phytochemistry 2018; 151: 1-8.
[72]
Khan D, Khan S, Badshah S, et al. New furocarbazole alkaloids from Lonicera quinquelocularis. Nat Prod Res 2016; 30(1): 74-8.
[73]
Karwehl S, Jansen R, Huch V, Stadler M. Sorazolons, Carbazole alkaloids from Sorangium cellulosum strain Soce375. J Nat Prod 2016; 79(2): 369-75.
[74]
Noolu B, Ajumeera R, Chauhan A, Nagalla B, Manchala R, Ismail A. Murraya koenigii leaf extract inhibits proteasome activity and induces cell death in breast cancer cells. BMC Complement Altern Med 2013; 13(1): 7.
[75]
Huang L, Feng Z-L, Wang Y-T, Lin L-G. Anticancer carbazole alkaloids and coumarins from Clausena plants: A review. Chin J Nat Med 2017; 15(12): 881-8.
[76]
Schmidt AW, Reddy KR, Knölker H-J. Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. Chem Rev 2012; 112(6): 3193-28.
[77]
Zheng X, Lv L, Lu S, Wang W, Li Z. Benzannulation of indoles to carbazoles and its applications for syntheses of carbazole alkaloids. Org Lett 2014; 16(19): 5156-9.
[78]
Sharma A, Das S, Pathak D, Sharma GK. Synthesis and pharmacological evaluation of tricyclic carbazole annulated with substituted benzothiazole2-amine under microwave irradiation. Biomed J Sci Tech Res 2018; 9(2): 1-9.
[79]
Shaikh M, Thapliyal N, Rane R, et al. Current perspective of natural alkaloid carbazole and its derivatives as antitumor agents. Anticancer Agents Med Chem 2015; 15(8): 1049-65.
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