Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

1-[4-(2-Dimethylaminoethoxy)phenylcarbonyl]-3,5-Bis(3,4,5-Trimethoxybenzylidene)- 4-Piperidone Hydrochloride and Related Compounds: Potent Cytotoxins Demonstrate Greater Toxicity to Neoplasms than Non- Malignant Cells

Author(s): Praveen K. Roayapalley*, Jonathan R. Dimmock*, Hiroshi Sakagami, Noriyki Okudaira, Rajendra K. Sharma and Umashankar Das

Volume 18, Issue 9, 2022

Published on: 23 May, 2022

Page: [1001 - 1012] Pages: 12

DOI: 10.2174/1573406418666220322154110

Price: $65

Abstract

Background: The incidence of cancer has been increasing worldwide. Unfortunately, the drugs used in cancer chemotherapy are toxic to both neoplasms and normal tissues, while many available medications have low potencies. Conjugated α,β-unsaturated ketones differ structurally from contemporary anticancer medications , some of which have noteworthy antineoplastic properties.

Objectives: This study aimed to design and synthesize highly potent cytotoxins with far greater toxicity to neoplasms than to non-malignant cells.

Methods: A series of N-acyl-3,5-bis(benzylidene)-4-piperidone hydrochlorides 4a-n were prepared and evaluated against Ca9-22, HSC-2, HSC-3, and HSC-4 squamous cell carcinomas as well as against HGF, HPLF, and HPC non-malignant cells. QSAR and western blot analyses were performed.

Results: The majority of compounds display submicromolar CC50 values towards the neoplasms; the figures for some of the compounds are below 10-7 M. In general, 4a-n have much lower CC50 values than those of melphalan, 5-fluorouracil, and methotrexate, while some compounds are equitoxic with doxorubicin. The compounds are far less toxic to the non-malignant cells, giving rise to substantial selectivity index (SI) figures. A QSAR study revealed that both potency and the SI data were controlled to a large extent by the electronic properties of the substituents in the arylidene aryl rings. Two representative compounds, 4f and 4g, caused apoptosis in HSC-2 cells.

Conclusion: The compounds in series 4 are potent cytotoxins displaying tumor-selective toxicity. In particular, 4g with an average CC50 value of 0.04 μM towards four malignant cell lines and a selectivity index of 46.3 is clearly a lead molecule that should be further evaluated.

Keywords: Cytotoxins, bioassays, apoptosis, organic syntheses, structure-activity relationships, neoplasms, selective toxicity.

Next »
Graphical Abstract

[1]
WHO fact sheets. Available from: https://www.who.int/health-topics/cancer#tab=tab_1 (Accessed on February 12, 2019).
[2]
Lei, X. Small molecule enabled chemical biology and drug discovery. Bioorg. Med. Chem., 2017, 25(11), 2815-2816.
[http://dx.doi.org/10.1016/j.bmc.2017.05.025] [PMID: 28532738]
[3]
Pan, W.; Hu, K.; Bai, P.; Yu, L.; Ma, Q.; Li, T.; Zhang, X.; Chen, C.; Peng, K.; Liu, W.; Sang, Z. De-sign, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2016, 26(10), 2539-2543.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.086] [PMID: 27072909]
[4]
Anighoro, A.; Bajorath, J.; Rastelli, G. Polypharmacology: Challenges and opportunities in drug dis-covery. J. Med. Chem., 2014, 57(19), 7874-7887.
[http://dx.doi.org/10.1021/jm5006463] [PMID: 24946140]
[5]
Martínez, A.; Zahran, M.; Gomez, M.; Cooper, C.; Guevara, J.; Ekengard, E.; Nordlander, E.; Alcen-dor, R.; Hambleton, S. Novel multi-target compounds in the quest for new chemotherapies against Alzheimer’s disease: An experimental and theoretical study. Bioorg. Med. Chem., 2018, 26(17), 4823-4840.
[http://dx.doi.org/10.1016/j.bmc.2018.08.019] [PMID: 30181028]
[6]
Raghavendra, N.M.; Pingili, D.; Kadasi, S.; Mettu, A.; Prasad, S.V.U.M. Dual or multi-targeting inhib-itors: The next generation anticancer agents. Eur. J. Med. Chem., 2018, 143, 1277-1300.
[http://dx.doi.org/10.1016/j.ejmech.2017.10.021] [PMID: 29126724]
[7]
Zheng, W.; Zhao, Y.; Luo, Q.; Zhang, Y.; Wu, K.; Wang, F. Multi-targeted anticancer agents. Curr. Top. Med. Chem., 2017, 17(28), 3084-3098.
[http://dx.doi.org/10.2174/1568026617666170707124126] [PMID: 28685693]
[8]
Chen, Z-F.; Orvig, C.; Liang, H. Multi-target metal-based anticancer agents. Curr. Top. Med. Chem., 2017, 17(28), 3131-3145.
[http://dx.doi.org/10.2174/1568026617666171004155437] [PMID: 28982336]
[9]
Ng, H-L.; Chen, S.; Chew, E-H.; Chui, W.K. Applying the designed multiple ligands approach to in-hibit dihydrofolate reductase and thioredoxin reductase for anti-proliferative activity. Eur. J. Med. Chem., 2016, 115, 63-74.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.002] [PMID: 26994844]
[10]
Fu, R.G.; Sun, Y.; Sheng, W.B.; Liao, D.F. Designing multi-targeted agents: An emerging anticancer drug discovery paradigm. Eur. J. Med. Chem., 2017, 136, 195-211.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.016] [PMID: 28494256]
[11]
Zha, G.F.; Qin, H.L.; Youssif, B.G.M.; Amjad, M.W.; Raja, M.A.G.; Abdelazeem, A.H.; Bukhari, S.N.A. Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance. Eur. J. Med. Chem., 2017, 135, 34-48.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.025] [PMID: 28431353]
[12]
Li, Y.; Qiang, X.; Luo, L.; Yang, X.; Xiao, G.; Zheng, Y.; Cao, Z.; Sang, Z.; Su, F.; Deng, Y. Multi-target drug design strategy against Alzheimer’s disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional proper-ties. Bioorg. Med. Chem., 2017, 25(2), 714-726.
[http://dx.doi.org/10.1016/j.bmc.2016.11.048] [PMID: 27923535]
[13]
Olsen, J.I.; Plata, G.B.; Padrón, J.M.; López, Ó.; Bols, M.; Fernández-Bolaños, J.G. Selenoureido-iminosugars: A new family of multitarget drugs. Eur. J. Med. Chem., 2016, 123, 155-160.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.021] [PMID: 27474931]
[14]
De Cesco, S.; Kurian, J.; Dufresne, C.; Mittermaier, A.K.; Moitessier, N. Covalent inhibitors design and discovery. Eur. J. Med. Chem., 2017, 138, 96-114.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.019] [PMID: 28651155]
[15]
Disney, M.D. Chemistry and chemical biology of therapeutically important compounds. Bioorg. Med. Chem., 2016, 24(17), 3875.
[http://dx.doi.org/10.1016/j.bmc.2016.06.049] [PMID: 27460698]
[16]
Amslinger, S. The tunable functionality of α,β-unsaturated carbonyl compounds enables their differ-ential application in biological systems. ChemMedChem, 2010, 5(3), 351-356.
[http://dx.doi.org/10.1002/cmdc.200900499] [PMID: 20112330]
[17]
Mah, R.; Thomas, J.R.; Shafer, C.M. Drug discovery considerations in the development of covalent inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(1), 33-39.
[http://dx.doi.org/10.1016/j.bmcl.2013.10.003] [PMID: 24314671]
[18]
Slawik, C.; Rickmeyer, C.; Brehm, M.; Böhme, A.; Schüürmann, G. Glutathione adduct patterns in Michael-acceptor carbonyls. Environ. Sci. Technol., 2017, 51(7), 4018-4026.
[http://dx.doi.org/10.1021/acs.est.6b04981] [PMID: 28225253]
[19]
Zhao, Z.; Liu, Q.; Bliven, S.; Xie, L.; Bourne, P.E. Determining cysteines available for covalent inhi-bition across the human kinome. J. Med. Chem., 2017, 60(7), 2879-2889.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01815] [PMID: 28326775]
[20]
Horiyama, S.; Hatai, M.; Takahashi, Y.; Date, S.; Masujima, T.; Honda, C.; Ichikawa, A.; Yoshikawa, N.; Nakamura, K.; Kunitomo, M.; Takayama, M. Intracellular metabolism of alpha,beta-unsaturated carbonyl compounds, acrolein, crotonaldehyde and methyl vinyl ketone, active toxicants in cigarette smoke: Participation of glutathione conjugation ability and aldehyde-ketone sensitive reductase activi-ty. Chem. Pharm. Bull. (Tokyo), 2016, 64(6), 585-593.
[http://dx.doi.org/10.1248/cpb.c15-00986] [PMID: 27250793]
[21]
Maydt, D.; De Spirt, S.; Muschelknautz, C.; Stahl, W.; Müller, T.J.J. Chemical reactivity and biologi-cal activity of chalcones and other α,β-unsaturated carbonyl compounds. Xenobiotica, 2013, 43(8), 711-718.
[http://dx.doi.org/10.3109/00498254.2012.754112] [PMID: 23339572]
[22]
Dimmock, J.R.; Shyam, K.; Hamon, N.W.; Logan, B.M.; Raghavan, S.K.; Harwood, D.J.; Smith, P.J. Evaluation of some Mannich bases derived from substituted acetophenones against P-388 lymphocyt-ic leukemia and on respiration in isolated rat liver mitochondria. J. Pharm. Sci., 1983, 72(8), 887-894.
[http://dx.doi.org/10.1002/jps.2600720812] [PMID: 6620142]
[23]
Mutus, B.; Wagner, J.D.; Talpas, C.J.; Dimmock, J.R.; Phillips, O.A.; Reid, R.S. 1-p-chlorophenyl-4,4-dimethyl-5-diethylamino-1-penten-3-one hydrobromide, a sulfhydryl-specific compound which reacts irreversibly with protein thiols but reversibly with small molecular weight thiols. Anal. Biochem., 1989, 177(2), 237-243.
[http://dx.doi.org/10.1016/0003-2697(89)90045-6] [PMID: 2729541]
[24]
Jenkins, G.J.S.; Doak, S.H.; Johnson, G.E.; Quick, E.; Waters, E.M.; Parry, J.M. Do dose response thresholds exist for genotoxic alkylating agents? Mutagenesis, 2005, 20(6), 389-398.
[http://dx.doi.org/10.1093/mutage/gei054] [PMID: 16135536]
[25]
Kaina, B.; Christmann, M.; Naumann, S.; Roos, W.P. MGMT: Key node in the battle against geno-toxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst.), 2007, 6(8), 1079-1099.
[http://dx.doi.org/10.1016/j.dnarep.2007.03.008] [PMID: 17485253]
[26]
Gan, F-F.; Kaminska, K.K.; Yang, H.; Liew, C-Y.; Leow, P-C.; So, C-L.; Tu, L.N.L.; Roy, A.; Yap, C-W.; Kang, T-S.; Chui, W-K.; Chew, E-H. Identification of Michael acceptor-centric pharmaco-phores with substituents that yield strong thioredoxin reductase inhibitory character correlated to an-tiproliferative activity. Antioxid. Redox Signal., 2013, 19(11), 1149-1165.
[http://dx.doi.org/10.1089/ars.2012.4909] [PMID: 23311917]
[27]
Safavy, A.; Raisch, K.P.; Mantena, S.; Sanford, L.L.; Sham, S.W.; Krishna, N.R.; Bonner, J.A. De-sign and development of water-soluble curcumin conjugates as potential anticancer agents. J. Med. Chem., 2007, 50(24), 6284-6288.
[http://dx.doi.org/10.1021/jm700988f] [PMID: 17973470]
[28]
Ai, Y.; Zhu, B.; Ren, C.; Kang, F.; Li, J.; Huang, Z.; Lai, Y.; Peng, S.; Ding, K.; Tian, J.; Zhang, Y. Discovery of new monocarbonyl-curcumin hybrids for intervention of drug-sensitive and drug-resistant lung cancer. J. Med. Chem., 2016, 59(5), 1747-1760.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01203] [PMID: 26891099]
[29]
Panda, A.K.; Das, U.; Umemura, N.; Sakagami, H.; Kawase, M.; Balzarini, J.; De Clercq, E.; Dim-mock, S.G.; Roayapalley, P.K.; Dimmock, J.R. 6-Benzylidene-2-[4-(pyridin-3-ylcarboxy) benzyli-dene]cyclohexanones: A novel cluster of tumour-selective cytotoxins. Bioorg. Med. Chem. Lett., 2017, 27(7), 1611-1615.
[http://dx.doi.org/10.1016/j.bmcl.2017.02.016] [PMID: 28238612]
[30]
Liang, B.; Liu, Z.; Cao, Y.; Zhu, C.; Zuo, Y.; Huang, L.; Wen, G.; Shang, N.; Chen, Y.; Yue, X.; Du, J.; Li, B.; Zhou, B.; Bu, X. MC37, a new mono-carbonyl curcumin analog, induces G2/M cell cycle ar-rest and mitochondria-mediated apoptosis in human colorectal cancer cells. Eur. J. Pharmacol., 2017, 796, 139-148.
[http://dx.doi.org/10.1016/j.ejphar.2016.12.030] [PMID: 28024945]
[31]
Kohyama, A.; Yamakoshi, H.; Hongo, S.; Kanoh, N.; Shibata, H.; Iwabuchi, Y. Structure-activity re-lationships of the antitumor C5-curcuminoid GO-Y030. Molecules, 2015, 20(8), 15374-15391.
[http://dx.doi.org/10.3390/molecules200815374] [PMID: 26305242]
[32]
Wang, R.; Chen, C.; Zhang, X.; Zhang, C.; Zhong, Q.; Chen, G.; Zhang, Q.; Zheng, S.; Wang, G.; Chen, Q-H. Structure-activity relationship and pharmacokinetic studies of 1,5-diheteroarylpenta-1,4-dien-3-ones: A class of promising curcumin-based anticancer agents. J. Med. Chem., 2015, 58(11), 4713-4726.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00470] [PMID: 25961334]
[33]
Ferrari, E.; Pignedoli, F.; Imbriano, C.; Marverti, G.; Basile, V.; Venturi, E.; Saladini, M. Newly syn-thesized curcumin derivatives: Crosstalk between chemico-physical properties and biological activity. J. Med. Chem., 2011, 54(23), 8066-8077.
[http://dx.doi.org/10.1021/jm200872q] [PMID: 22029378]
[34]
Qiu, X.; Du, Y.; Lou, B.; Zuo, Y.; Shao, W.; Huo, Y.; Huang, J.; Yu, Y.; Zhou, B.; Du, J.; Fu, H.; Bu, X. Synthesis and identification of new 4-arylidene curcumin analogues as potential anticancer agents targeting nuclear factor-κB signaling pathway. J. Med. Chem., 2010, 53(23), 8260-8273.
[http://dx.doi.org/10.1021/jm1004545] [PMID: 21070043]
[35]
Chen, G.; Waxman, D.J. Role of cellular glutathione and glutathione S-transferase in the expression of alkylating agent cytotoxicity in human breast cancer cells. Biochem. Pharmacol., 1994, 47(6), 1079-1087.
[http://dx.doi.org/10.1016/0006-2952(94)90420-0] [PMID: 8147907]
[36]
Tsutsui, K.; Komuro, C.; Ono, K.; Nishidai, T.; Shibamoto, Y.; Takahashi, M.; Abe, M. Chemosensiti-zation by buthionine sulfoximine in vivo. Int. J. Radiat. Oncol. Biol. Phys., 1986, 12(7), 1183-1186.
[http://dx.doi.org/10.1016/0360-3016(86)90254-3] [PMID: 2427490]
[37]
Das, S.; Das, U.; Sakagami, H.; Hashimoto, K.; Kawase, M.; Gorecki, D.K.J.; Dimmock, J.R. Sequen-tial cytotoxicity: A theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids. Bioorg. Med. Chem. Lett., 2010, 20(22), 6464-6468.
[http://dx.doi.org/10.1016/j.bmcl.2010.09.051] [PMID: 20889340]
[38]
Dimmock, J.R.; Kandepu, N.M.; Nazarali, A.J.; Motaganahalli, N.L.; Kowalchuk, T.P.; Pugazhenthi, U.; Prisciak, J.S.; Quail, J.W.; Allen, T.M.; LeClerc, R.; Santos, C.L.; De Clercq, E.; Balzarini, J. Se-quential cytotoxicity: A theory evaluated using novel 2-[4-(3-aryl-2-propenoyloxy)phenylmethylene]cyclohexanones and related compounds. J. Med. Chem., 2000, 43(21), 3933-3940.
[http://dx.doi.org/10.1021/jm000058o] [PMID: 11052798]
[39]
Contreras, L.; Calderon, R.I.; Varela-Ramirez, A.; Zhang, H-Y.; Quan, Y.; Das, U.; Dimmock, J.R.; Skouta, R.; Aguilera, R.J. Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones. Cell Oncol. (Dordr.), 2018, 41(6), 623-636.
[http://dx.doi.org/10.1007/s13402-018-0397-1] [PMID: 30088262]
[40]
Addala, E.; Rafiei, H.; Das, S.; Bandy, B.; Das, U.; Karki, S.S.; Dimmock, J.R. 3,5-Bis(3-dimethylaminomethyl-4-hydroxybenzylidene)-4-piperidone and related compounds induce glutathi-one oxidation and mitochondria-mediated cell death in HCT-116 colon cancer cells. Bioorg. Med. Chem. Lett., 2017, 27(16), 3669-3673.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.018] [PMID: 28716495]
[41]
Santiago-Vázquez, Y.; Das, U.; Varela-Ramirez, A.; Baca, S.T.; Ayala-Marin, Y.; Lema, C.; Das, S.; Baryyan, A.; Dimmock, J.R.; Aguilera, R.J. Tumor-selective cytotoxicity of a novel pentadiene ana-logue on human leukemia/lymphoma cells. Clin. Cancer Drugs, 2016, 3(2), 138-146.
[http://dx.doi.org/10.2174/2212697X03666160830165250] [PMID: 27857884]
[42]
Hossain, M.; Das, U.; Umemura, N.; Sakagami, H.; Balzarini, J.; De Clercq, E.; Kawase, M.; Dim-mock, J.R. Tumour-specific cytotoxicity and structure-activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones. Bioorg. Med. Chem., 2016, 24(10), 2206-2214.
[http://dx.doi.org/10.1016/j.bmc.2016.03.056] [PMID: 27073056]
[43]
Das, U.; Pati, H.N.; Baráth, Z.; Csonka, Á.; Molnár, J.; Dimmock, J.R. 1-[3-(2-Hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzyli-dene)-4-piperidones: A novel cluster of P-glycoprotein dependent multidrug resistance modulators. Bioorg. Med. Chem. Lett., 2016, 26(4), 1319-1321.
[http://dx.doi.org/10.1016/j.bmcl.2016.01.005] [PMID: 26796064]
[44]
Karki, S.S.; Das, U.; Umemura, N.; Sakagami, H.; Iwamoto, S.; Kawase, M.; Balzarini, J.; De Clercq, E.; Dimmock, S.G.; Dimmock, J.R. 3,5-Bis(3-alkylaminomethyl-4-hydroxybenzylidene)-4-piperidones: A novel class of potent tumor-selective cytotoxins. J. Med. Chem., 2016, 59(2), 763-769.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01706] [PMID: 26727215]
[45]
Robles-Escajeda, E.; Das, U.; Ortega, N.M.; Parra, K.; Francia, G.; Dimmock, J.R.; Varela-Ramirez, A.; Aguilera, R.J. A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells. Cell Oncol. (Dordr.), 2016, 39(3), 265-277.
[http://dx.doi.org/10.1007/s13402-016-0272-x] [PMID: 26920032]
[46]
Nunes, L.M.; Hossain, M.; Varela-Ramirez, A.; Das, U.; Ayala-Marin, Y.M.; Dimmock, J.R.; Aguilera, R.J. A novel class of piperidones exhibit potent, selective and pro-apoptotic anti-leukemia properties. Oncol. Lett., 2016, 11(6), 3842-3848.
[http://dx.doi.org/10.3892/ol.2016.4480] [PMID: 27313705]
[47]
Edraki, N.; Das, U.; Hemateenejad, B.; Dimmock, J.R.; Miri, R. Comparative QSAR analysis of 3,5-bis(arylidene)-4-piperidone derivatives: The development of predictive cytotoxicity models. Iran. J. Pharm. Res., 2016, 15(2), 425-437.
[PMID: 27642313]
[48]
Das, U.; Pati, H.N.; Sakagami, H.; Hashimoto, K.; Kawase, M.; Balzarini, J.; De Clercq, E.; Dim-mock, J.R. 3,5-Bis(benzylidene)-1-[3-(2-hydroxyethylthio)propanoyl]piperidin-4-ones: A novel cluster of potent tumor-selective cytotoxins. J. Med. Chem., 2011, 54(9), 3445-3449.
[http://dx.doi.org/10.1021/jm101595p] [PMID: 21449610]
[49]
Li, N.; Xin, W-Y.; Yao, B-R.; Wang, C-H.; Cong, W.; Zhao, F.; Li, H-J.; Hou, Y.; Meng, Q-G.; Hou, G-G. Novel dissymmetric 3,5-bis(arylidene)-4-piperidones as potential antitumor agents with biologi-cal evaluation in vitro and in vivo. Eur. J. Med. Chem., 2018, 147, 21-33.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.088] [PMID: 29421568]
[50]
Li, N.; Xin, W-Y.; Yao, B-R.; Cong, W.; Wang, C-H.; Hou, G-G. N-phenylsulfonyl-3,5-bis(arylidene)-4-piperidone derivatives as activation NF-κB inhibitors in hepatic carcinoma cell lines. Eur. J. Med. Chem., 2018, 155, 531-544.
[http://dx.doi.org/10.1016/j.ejmech.2018.06.027] [PMID: 29909338]
[51]
Chen, W.; Zou, P.; Zhao, Z.; Chen, X.; Fan, X.; Vinothkumar, R.; Cui, R.; Wu, F.; Zhang, Q.; Liang, G.; Ji, J. Synergistic antitumor activity of rapamycin and EF24 via increasing ROS for the treatment of gastric cancer. Redox Biol., 2016, 10, 78-89.
[http://dx.doi.org/10.1016/j.redox.2016.09.006] [PMID: 27697670]
[52]
Bazzaro, M.; Anchoori, R.K.; Mudiam, M.K.R.; Issaenko, O.; Kumar, S.; Karanam, B.; Lin, Z. Isaks-son Vogel, R.; Gavioli, R.; Destro, F.; Ferretti, V.; Roden, R.B.S.; Khan, S.R. α,β-Unsaturated car-bonyl system of chalcone-based derivatives is responsible for broad inhibition of proteasomal activity and preferential killing of Human Papilloma Virus (HPV) positive cervical cancer cells. J. Med. Chem., 2011, 54(2), 449-456.
[http://dx.doi.org/10.1021/jm100589p] [PMID: 21186794]
[53]
Feng, C.; Xia, Y.; Zou, P.; Shen, M.; Hu, J.; Ying, S.; Pan, J.; Liu, Z.; Dai, X.; Zhuge, W.; Liang, G.; Ruan, Y. Curcumin analog L48H37 induces apoptosis through ROS-mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells. Mol. Carcinog., 2017, 56(7), 1765-1777.
[http://dx.doi.org/10.1002/mc.22633] [PMID: 28218464]
[54]
Zhang, W.; Bai, H.; Han, L.; Zhang, H.; Xu, B.; Cui, J.; Wang, X.; Ge, Z.; Li, R. Synthesis and bio-logical evaluation of curcumin derivatives modified with α-amino boronic acid as proteasome inhibi-tors. Bioorg. Med. Chem. Lett., 2018, 28(14), 2459-2464.
[http://dx.doi.org/10.1016/j.bmcl.2018.06.004] [PMID: 29886021]
[55]
Qiu, C.; Hu, Y.; Wu, K.; Yang, K.; Wang, N.; Ma, Y.; Zhu, H.; Zhang, Y.; Zhou, Y.; Chen, C.; Li, S.; Fu, L.; Zhang, X.; Liu, Z. Synthesis and biological evaluation of allylated mono-carbonyl analogues of curcumin (MACs) as anti-cancer agents for cholangiocarcinoma. Bioorg. Med. Chem. Lett., 2016, 26(24), 5971-5976.
[http://dx.doi.org/10.1016/j.bmcl.2016.10.080] [PMID: 27825763]
[56]
Das, U.; Alcorn, J.; Shrivastav, A.; Sharma, R.K.; De Clercq, E.; Balzarini, J.; Dimmock, J.R. Design, synthesis and cytotoxic properties of novel 1-[4-(2-alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones and related compounds. Eur. J. Med. Chem., 2007, 42(1), 71-80.
[http://dx.doi.org/10.1016/j.ejmech.2006.08.002] [PMID: 16996657]
[57]
Das, S.; Das, U.; Michel, D.; Gorecki, D.K.J.; Dimmock, J.R. Novel 3,5-bis(arylidene)-4-piperidone dimers: Potent cytotoxins against colon cancer cells. Eur. J. Med. Chem., 2013, 64, 321-328.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.055] [PMID: 23644215]
[58]
Dimmock, J.R.; Padmanilayam, M.P.; Puthucode, R.N.; Nazarali, A.J.; Motaganahalli, N.L.; Zello, G.A.; Quail, J.W.; Oloo, E.O.; Kraatz, H-B.; Prisciak, J.S.; Allen, T.M.; Santos, C.L.; Balzarini, J.; De Clercq, E.; Manavathu, E.K. A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues. J. Med. Chem., 2001, 44(4), 586-593.
[http://dx.doi.org/10.1021/jm0002580] [PMID: 11170648]
[59]
Hansch, C.; Leo, A.J. Substituent Constants for Correlation Analysis in Chemistry and Biology; John Wiley and Sons: New York, 1979, p. 49.
[60]
Hansch, C.; Leo, A.J. Substituent Constants for Correlation Analysis in Chemistry and Biology; John Wiley and Sons: New York, 1979, p. 84.
[61]
Taft, R.W., Jr Separation of polar, steric and resonance effects in reactivity. In: Steric Effects in Or-ganic Chemistry; Newman, M.S., Ed.; John Wiley and Sons, Inc.: New York, 1956; p. 591.
[62]
Statistical Package for Social Sciences, SPSS for windows, Release 17.0, SPSS. Chicago, 2008. Available from: https://www.unige.ch/ses/sococ/cl/bib/soft/spss.history.html
[63]
Motohashi, N.; Wakabayashi, H.; Kurihara, T.; Fukushima, H.; Yamada, T.; Kawase, M.; Sohara, Y.; Tani, S.; Shirataki, Y.; Sakagami, H.; Satoh, K.; Nakashima, H.; Molnár, A.; Spengler, G.; Gyémánt, N.; Ugocsai, K.; Molnár, J. Biological activity of barbados cherry (acerola fruits, fruit of Malpighia emarginata DC) extracts and fractions. Phytother. Res., 2004, 18(3), 212-223.
[http://dx.doi.org/10.1002/ptr.1426] [PMID: 15103668]
[64]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[65]
Lagisetly, P.; Powell, D.R.; Awasthi, V. Synthesis and structural determination of 3,5-bis(2-fluorobenzylidene)-4-piperidone analogs of curcumin. J. Mol. Struct., 2009, 936, 23-28.
[http://dx.doi.org/10.1016/j.molstruc.2009.07.016]
[66]
Dimmock, J.R.; Kandepu, N.M.; Nazarali, A.J.; Kowalchuk, T.P.; Motaganahalli, N.; Quail, J.W.; Mykytiuk, P.A.; Audette, G.F.; Prasad, L.; Perjési, P.; Allen, T.M.; Santos, C.L.; Szydlowski, J.; De Clercq, E.; Balzarini, J. Conformational and quantitative structure-activity relationship study of cyto-toxic 2-arylidenebenzo-cycloalkanones. J. Med. Chem., 1999, 42(8), 1358-1366.
[http://dx.doi.org/10.1021/jm9806695] [PMID: 10212121]
[67]
Hassner, A.; Mead, T.C. The stereochemistry of 2-benzalcyclohexanones and 2-benzalcyclopentanones. Tetrahedron, 1964, 20, 2201-2210.
[http://dx.doi.org/10.1016/S0040-4020(01)97605-7]
[68]
Dimmock, J.R.; Arora, V.K.; Wonko, S.L.; Hamon, N.W.; Quail, J.W.; Jia, Z.; Warrington, R.C.; Fang, W.D.; Lee, J.S. 3,5-Bis-benzylidene-4-piperidones and related compounds with high activity towards P388 leukemia cells. Drug Des. Deliv., 1990, 6(3), 183-194.
[PMID: 2076179]
[69]
Dimmock, J.R.; Kumar, P.; Chen, M.; Quail, J.W.; Yang, J.; Allen, T.M.; Kao, G.Y. Synthesis and cytotoxic evaluation of mesna adducts of some 1-aryl-4,4-dimethyl-5-(1-piperidino)-1-penten-3-one hydrochlorides. Pharmazie, 1995, 50(7), 449-453.
[http://dx.doi.org/10.1002/chin.199544147] [PMID: 7675885]
[70]
Dimmock, J.R.; Raghavan, S.K.; Logan, B.M.; Bigam, G.E. Antileukemic evaluation of some Man-nich bases derived from 2-arylidene-1,3-diketones. Eur. J. Med. Chem., 1983, 18, 248-254.
[71]
Dimmock, J.R.; Phillips, O.A.; Wonko, S.L.; Hickie, R.A.; Tuer, R.G.; Ambrose, S.J.; Reid, R.S.; Mu-tus, B.; Talpas, C.L. Evaluation of some Mannich bases of conjugated styryl ketones and related com-pounds versus the WiDr colon cancer in vitro. Eur. J. Med. Chem., 1989, 24, 217-226.
[http://dx.doi.org/10.1016/0223-5234(89)90002-0]
[72]
Lu, Y.; Chen, J.; Xiao, M.; Li, W.; Miller, D.D. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm. Res., 2012, 29(11), 2943-2971.
[http://dx.doi.org/10.1007/s11095-012-0828-z] [PMID: 22814904]
[73]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[74]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational ap-proaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[75]
Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular proper-ties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]

Rights & Permissions Print Cite
Article Metrics
33
1
© 2024 Bentham Science Publishers | Privacy Policy