Abstract
Background: The prospective uses of tryptanthrin and its analogues in cancer chemotherapy are well known, and they are also predicated on their capacity to reverse drug resistance in cancer therapy.
Objective: The current project entails developing a novel hybrid analogue that includes modifying the tryptanthrin molecule at the C-6 carbonyl position and is expected to exhibit substantial anticancer action.
Methods: In the ATPase domain of human topoisomerase II, a series of 162 substituted Schiff base analogues of tryptanthrin were developed, and molecular docking experiments were done using Gold 5.1 software interfaced with Hermes 1.6.2. (PDB ID: 1ZXM).
Results: Most of the compounds were found to have Goldscore above 100 and formed interactions with the residues like ASN91, ALA92, ASN95, ARG98, ASN120, ILE125, ILE141, PHE142, SER149, THR215, and ILE217. Compound RK-149 had highest Goldscore of 132.59, forming an interaction with ASN91 but had a lesser Goldscore as compared to the standard drug etoposide and had a better score than tryptanthrin.
Conclusion: The nitrogen in the imine bond of the proposed compounds is responsible for significant interactions, demonstrating their anticancer potential.
Graphical Abstract
[http://dx.doi.org/10.1055/s-2008-1074877] [PMID: 7367492]
[http://dx.doi.org/10.1016/S0040-4039(01)82284-X]
[http://dx.doi.org/10.1016/S0040-4020(01)96609-8]
[http://dx.doi.org/10.1021/np800064w] [PMID: 18507473]
[http://dx.doi.org/10.1023/A:1007082619328] [PMID: 10721515]
[http://dx.doi.org/10.3998/ark.5550190.0013.113]
[http://dx.doi.org/10.1021/np020019a] [PMID: 12444694]
[http://dx.doi.org/10.1007/BF00979651] [PMID: 24248563]
[http://dx.doi.org/10.1055/s-0028-1097320] [PMID: 515225]
[http://dx.doi.org/10.1016/S0968-0896(02)00013-5] [PMID: 11937358]
[http://dx.doi.org/10.1248/bpb.28.260] [PMID: 15684480]
[http://dx.doi.org/10.1248/bpb.b14-00363] [PMID: 25273386]
[http://dx.doi.org/10.1016/j.jep.2010.12.041] [PMID: 21216280]
[http://dx.doi.org/10.1248/bpb.26.365] [PMID: 12612449]
[http://dx.doi.org/10.1016/S1567-5769(01)00206-5] [PMID: 11962735]
[http://dx.doi.org/10.1055/s-2001-15805] [PMID: 11488453]
[http://dx.doi.org/10.1016/S0960-894X(02)00431-6] [PMID: 12161121]
[http://dx.doi.org/10.1046/j.1440-1827.2001.01204.x] [PMID: 11422788]
[PMID: 11848486]
[http://dx.doi.org/10.18433/J3501W] [PMID: 21824448]
[http://dx.doi.org/10.2174/157489106775244163] [PMID: 18221132]
[http://dx.doi.org/10.1021/jm901847f] [PMID: 20373766]
[http://dx.doi.org/10.3109/15376516.2013.859194] [PMID: 24156546]
[http://dx.doi.org/10.1021/np500108r] [PMID: 24885014]
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a022367] [PMID: 10220582]
[http://dx.doi.org/10.1021/ci800081s] [PMID: 18816046]
[http://dx.doi.org/10.2174/1573409052952314]
[http://dx.doi.org/10.1016/j.bmc.2012.06.034] [PMID: 22819942]
[http://dx.doi.org/10.2174/157340911795677602] [PMID: 21534921]
[http://dx.doi.org/10.1002/ardp.201800023] [PMID: 29737542]
[http://dx.doi.org/10.1021/acs.jcim.0c00202] [PMID: 32484690]
[http://dx.doi.org/10.1021/acs.jmedchem.9b00726] [PMID: 31592646]
[http://dx.doi.org/10.1371/journal.pone.0107289] [PMID: 25202966]
[http://dx.doi.org/10.1016/j.molstruc.2022.133977];
b) Konar, D.; Maru, S.; Kar, S.; Kumar, K. Synthesis and clinical development of palbociclib: An overview. Med. Chem., 2022, 18(1), 2-25.
[http://dx.doi.org/10.2174/1573406417666201204161243] [PMID: 33280599];
c) Pawar, S.; Kumar, K.; Gupta, M.K.; Rawal, R.K. Synthetic and medicinal perspective of fused-thiazoles as anticancer agents. Anticancer. Agents Med. Chem., 2021, 21(11), 1379-1402.
[http://dx.doi.org/10.2174/1871520620666200728133017] [PMID: 32723259];
d) Kaur, R.; Kumar, K. Synthetic and medicinal perspective of quinolines as antiviral agents. Eur. J. Med. Chem., 2021, 215, 113220-113258.
[http://dx.doi.org/10.1016/j.ejmech.2021.113220] [PMID: 33609889];
e) Kapoor, Y.; Kumar, K. Structural and clinical impact of antiallergy agents: An overview. Bioorg. Chem., 2020, 94, 103351-103375.
[http://dx.doi.org/10.1016/j.bioorg.2019.103351] [PMID: 31668464];
f) Kaur, R.; Manjal, S.K.; Rawal, R.K.; Kumar, K. Recent synthetic and medicinal perspectives of tryptanthrin. Bioorg. Med. Chem., 2017, 25(17), 4533-4552.
[http://dx.doi.org/10.1016/j.bmc.2017.07.003] [PMID: 28720329];
g) Kaur, M.S.; Kaur, R.; Bhatia, R.; Kumar, K.; Singh, V.; Shankar, R.; Kaur, R.; Rawal, R.K. Synthetic and medicinal perspective of thiazolidinones: A review. Bioorg. Chem., 2017, 75, 406-423.
[http://dx.doi.org/10.1016/j.bioorg.2017.10.014] [PMID: 29102723];
h) Kaur, R.; Chaudhary, S.; Kumar, K.; Gupta, M.K.; Rawal, R.K. Recent synthetic and medicinal perspectives of dihydropyrimidinones: A review. Eur. J. Med. Chem., 2017, 132, 108-134.
[http://dx.doi.org/10.1016/j.ejmech.2017.03.025] [PMID: 28342939];
i) Kumar, B.; Singh, V.; Shankar, R.; Kumar, K.; Rawal, R. Synthetic and medicinal prospective of structurally modified curcumins. Curr. Top. Med. Chem., 2016, 17(2), 148-161.
[http://dx.doi.org/10.2174/1568026616666160605050052] [PMID: 27280465];
j) Mittal, M.; Kumar, K.; Anghore, D.; Rawal, R.K. ICP-MS: Analytical method for identification and detection of elemental impurities. Curr. Drug Discov. Technol., 2017, 14(2), 106-120.
[http://dx.doi.org/10.2174/1570163813666161221141402] [PMID: 28003007];
k) Talwan, P.; Choudhary, S.; Kumar, K.; Rawal, R.K. Chemical and medicinal versatility of substituted 1, 4-dihydropyridines. Curr. Bioact. Compd., 2017, 13, 109-120.
[http://dx.doi.org/10.2174/1573407212666160607090202]
[http://dx.doi.org/10.1002/jhet.4376];
b) Kumar, K. TosMIC: A powerful synthon for cyclization and sulfonylation. Chem. Select, 2020, 5(33), 10298-10328.
[http://dx.doi.org/10.1002/slct.202001344];
c) Kaur, R.; Kapoor, Y.; Manjal, S.K.; Rawal, R.K.; Kumar, K. Diversity-oriented synthetic approaches for furoindoline: A review. Curr. Org. Synth., 2019, 16(3), 342-368.
[http://dx.doi.org/10.2174/1570179416666190328211509] [PMID: 31984898];
d) Manjal, S.K.; Pathania, S.; Bhatia, R.; Kaur, R.; Kumar, K.; Rawal, R.K. Diversified synthetic strategies for pyrroloindoles: An overview. J. Heterocycl. Chem., 2019, 56(9), 2318-2332.
[http://dx.doi.org/10.1002/jhet.3661]
[http://dx.doi.org/10.1002/slct.201903703];
b) Kaur, R.; Kumar, K. One-pot synthesis of [4-(tert-butyl)-1Hpyrrol- 3-yl](phenyl)methanone from tosylmethyl isocyanide and carbonyl compound. Chem. Heterocycl. Compd., 2018, 54(7), 700-702.
[http://dx.doi.org/10.1007/s10593-018-2335-6];
c) Kumar, K.; More, S.S.; Khatik, G.L.; Rawal, R.K.; Nair, V.A. A highly stereoselective chiral auxiliary-assisted reductive cyclization to furoindoline. J. Heterocycl. Chem., 2017, 54(5), 2696-2702.
[http://dx.doi.org/10.1002/jhet.2870];
d) Kumar, K.; Konar, D.; Goyal, S.; Gangar, M.; Chouhan, M.; Rawal, R.K.; Nair, V.A. Water-promoted regiospecific azidolysis and copper-catalyzed azide–alkyne cycloaddition: One-pot synthesis of 3-hydroxy-1-alkyl-3-[(4-aryl/alkyl-1 H -1,2,3-triazol-1- yl)methyl]indolin-2-ones. J. Org. Chem., 2016, 81(20), 9757-9764.
[http://dx.doi.org/10.1021/acs.joc.6b01819] [PMID: 27657181];
e) Kumar, K.; Siddique, J.; Gangar, M.; Goyal, S.; Rawal, R.K.; Nair, V.A. ZrCl4 catalysed diastereoselective synthesis of spirocarbocyclic oxindoles via [4+2] cycloaddition. Chem. Select, 2016, 1(10), 2409-2412.
[http://dx.doi.org/10.1002/slct.201600447];
f) Kumar, K.; Konar, D.; Goyal, S.; Gangar, M.; Chouhan, M.; Rawal, R.K.; Nair, V.A. AlCl3/Cyclohexane mediated electrophilic activation of isothiocyanates: An efficient synthesis of thioamides. Chem. Select, 2016, 1(12), 3228-3231.
[http://dx.doi.org/10.1002/slct.201600601];
g) Kumar, K.; More, S.S.; Goyal, S.; Gangar, M.; Khatik, G.L.; Rawal, R.K.; Nair, V.A. A convenient synthesis of 4-alkyl-3- benzoylpyrroles from α,β-unsaturated ketones and tosylmethyl isocyanide. Tetrahedron Lett., 2016, 57(21), 2315-2319.
[http://dx.doi.org/10.1016/j.tetlet.2016.04.056];
h) Kumar, K.; Mudshinge, S.R.; Goyal, S.; Gangar, M.; Nair, V.A. A catalyst free, one pot approach for the synthesis of quinoxaline derivatives via oxidative cyclisation of 1,2-diamines and phenacyl bromides. Tetrahedron Lett., 2015, 56(10), 1266-1271.
[http://dx.doi.org/10.1016/j.tetlet.2015.01.138];
i) Goyal, S.; Patel, J.K.; Gangar, M.; Kumar, K.; Nair, V.A. Zirconocene dichloride catalysed one-pot synthesis of pyrroles through nitroalkene-enamine assembly. RSC Advances, 2015, 5(5), 3187-3195.
[http://dx.doi.org/10.1039/C4RA09873K];
j) Goyal, S.; Patel, B.; Sharma, R.; Chouhan, M.; Kumar, K.; Gangar, M.; Nair, V.A. An efficient strategy for the synthesis of syn 1,3-diols via iterative acetate aldol reactions and synthesis of atorvastatin lactone. Tetrahedron Lett., 2015, 56(40), 5409-5412.
[http://dx.doi.org/10.1016/j.tetlet.2015.08.011];
k) Gangar, M.; Kashyap, N.; Kumar, K.; Goyal, S.; Nair, V.A. Imidazolidinone based chiral auxiliary mediated acetate aldol reactions of isatin derivatives and stereoselective synthesis of 3- substituted-3-hydroxy-2-oxindoles. Tetrahedron Lett., 2015, 56(51), 7074-7081.
[http://dx.doi.org/10.1016/j.tetlet.2015.11.007];
l) Chouhan, M.; Senwar, K.R.; Kumar, K.; Sharma, R.; Nair, V.A. Catalytic C-H activation of arylacetylenes: A fast assembly of 3- hydroxy-3-(arylethynyl)indolin-2-ones using CuI/DBU. Synthesis, 2014, 46(2), 195-202.;
m) Kumar, V.; Kumar, K.; Pal, A.; Khatik, G.L.; Nair, V.A. Aldol reactions of 2-thioxotetrahydropyrimidin-4(1H)-ones: Stereoregulations from endo- and exocyclic chiral centres. Tetrahedron, 2013, 69(6), 1747-1754.
[http://dx.doi.org/10.1016/j.tet.2012.12.020];
n) Sharma, R.; Kumar, K.; Chouhan, M.; Grover, V.; Nair, V.A. Lithium hydroxide mediated synthesis of 3,4-disubstituted pyrroles. RSC Advances, 2013, 3(34), 14521-14527.
[http://dx.doi.org/10.1039/c3ra42569j];
o) Chouhan, M.; Kumar, K.; Sharma, R.; Grover, V.; Nair, V.A. NiCl2·6H2O/NaBH4 in methanol: A mild and efficient strategy for chemoselective deallylation/debenzylation of aryl ethers. Tetrahedron Lett., 2013, 54(34), 4540-4543.
[http://dx.doi.org/10.1016/j.tetlet.2013.06.072]