Synthesis and Cytotoxic Evaluation of Homoveratrylamine-Based Derivatives Derived from Carboxylic Acids
DOI:
https://doi.org/10.37134/jsml.vol14.2.3.2026Keywords:
Isoquinoline derivatives , Homoveratrylamine , Carboxylic acid, Cytotoxicity, Сancer cellAbstract
Condensation reactions between homoveratrilamine and various carboxylic acids provide an efficient route to structurally diverse amide and isoquinoline derivatives with potential biological activity. In this study, a series of amides and 1-substituted dihydro- and tetrahydroisoquinolines were synthesized from homoveratrilamine and itaconic acid, mandelic acid, cinnamic acid, m-iodobenzoic acid, 2,4-dinitrobenzoic acid, and 2,4-dichlorobenzoic acid. Amides (4, 5, and 12) and 1-substituted dihydro- (6, 13-16) and tetrahydroisoquinolines (17) were successfully obtained. The cytotoxic activity of the synthesized compounds was evaluated in vitro using the MTT assay against four human cancer cell lines cervical carcinoma (HeLa), mammary adenocarcinoma (HBL-100), laryngeal adenocarcinoma (HEp-2), and T-lymphoblastic leukemia (CCRF-CEM) as well as three non-malignant cell lines, including African green monkey kidney (Vero B) cells, rat embryonic fibroblasts, and rat hepatocytes. The antitumor drug cisplatin was used as a positive control. Proliferative activity was identified for dihydroisoquinolines differing in substituents in the aromatic moiety. This effect emerged and increased in the following order: iodophenyl < dichloro < dinitro < dimethoxy. The transition from dihydroisoquinoline 15 to tetrahydroisoquinoline 17, while retaining the iodophenyl fragment in the structure, also led to the appearance of proliferative properties in cervical carcinoma cells, resulting in an 18% increase in proliferation. Among all tested derivatives, the itaconic acid-based dihydroisoquinolines 6 exhibited the most pronounced cytotoxic activity against HeLa, HBL-100, and HEp-2 cells, with IC₅₀ values of 24.9, 13.1, and 27.1 μM, respectively. Notably, it exhibited considerably lower cytotoxicity toward Vero B cells and hepatocytes, with IC₅₀ values of 95.9 and 100 μM, respectively; however, it proved to be highly toxic to skin fibroblasts (IC₅₀ = 12.6 μM). These results indicate that the itaconic acid dihydroisoquinoline derivative demonstrates pronounced selective cytotoxicity toward cancer cells while largely sparing normal cells, highlighting its potential as a promising lead compound for further optimization.
Downloads
References
Aghekyan AA, Arakelyan EA, Panosyan GA, Khachatryan AG, Markaryan EA. (2009). Synthesis of novel 1,2-functionally-substituted 6,7-dimethoxy-4-spirocyclo-pentanetetrahydroisoquinolines. Chemistry of Heterocyclic Compounds, 45(9), 1069-1074. doi:10.1007/s10593-009-0385-5
Azamatov AA, Zhurakulov ShN, Vinogradova VI, Tursunkhodzhaeva FM, Khinkar RM, Malatani RT, Aldurdunji MM, Tiezzi A, Mamadalieva NZ. (2023). Evaluation of the local anesthetic activity, acute toxicity, and structure-toxicity relationship in series of synthesized 1-aryltetrahydroisoquinoline alkaloid derivatives in vivo and in silico. Molecules, 28, 477-494. doi:10.3390/molecules28020477
Basak D, Arrighi S, Darwiche Ya, Deb S. (2021). Comparison of anticancer drug toxicities: Paradigm shift in adverse effect profile. Life, 12(1), 48. doi:10.3390/life12010048
Cabral F, Miller CM, Kudrna KM, Hass BE, Daubendiek JG, Kellar BM, Harris EN. (2018). Purification of hepatocytes and sinusoidal endothelial cells from mouse liver perfusion. Journal of Visualized Experiments, 132, e56993. doi:10.3791/56993
Darji P, Patel J,.Patel B, Chudasama A, Fnu PI, Nalla S. (2024). A comprehensive review on anticancer natural drugs. World Journal of Pharmacy and Pharmaceutical Sciences, 13(4), 717-734. doi:10.20959/wjpps20244-27049
Demir-Yazici K, Guzel-Akdemir O. (2022). Synthesis and potential antitumor activities of mandelic acid linked 2-aryl-1,3-thiazolidin-4-ones. Journal of Research in Pharmacy, 26(4), 931-940. https://doi.org/10.29228/jrp.191
Diaz G, Miranda IL, Diaz MA. (2015). Quinolines, isoquinolines, angustureine, and congeneric alkaloids-occurrence, chemistry, and biological activity. Phytochemicals - Isolation, Characterisation and Role in Human Health, IntechOpen, p. 141-162. doi:10.5772/59819
Dusmatova DE, Terent’eva EO, Bobakulov KhM, Mukhamatkhanova RF, Tsai EA, Tashkhodzhaev B, Sham’yanov ID, Azimova ShS, Abdullaev ND. (2019). Nonpolar constituents of Inula grandis roots cytotoxic activity of Igalan. Chemistry of Natural Compounds, 55(3), 571-574. doi:10.1007/s10600-019-02747-y
Dy GK, Adjei AA. (2013). Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA: A Cancer Journal for Clinicians, 63(4), 249-79. doi:10.3322/caac.21184
Eijl S, Zhu Zh, Cupitt J, Gierula M, Götz Ch, Fritsche E, Edwards RJ. (2012). Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling. PLoS One, 7, e41721. doi: 10.1371/journal.pone.0041721
Freidlina RK, Velichko FK, Chukovskaya ET, Khorlina MY, Krentsel BA., Il'ina DE, Gasanov RG. (1973). Methods of Heteroorganic Chemistry, Chlorine, Aliphatic Compounds, Moscow, Russia.
Girek M, Kłosiński K, Grobelski B, Pizzimenti S, Cucci MA, Daga M, Barrera G, Pasieka Z, Czarnecka K, Szymański P. (2019). Novel tetrahydroacridine derivatives with iodobenzoic moieties induce G0/G1 cell cycle arrest and apoptosis in A549 non-small lung cancer and HT-29 colorectal cancer cells. Molecular and Cellular Biochemistry, 460(1), 123-150. doi:10.1007/s11010-019-03576-x
Gurjar MK, Pramanik C, Bhattasali D, Ramana CV, Mohapatra DK. (2007). Total syntheses of schulzeines B and C. The Journal of Organic Chemistry, 72(17), 6591-6594. doi:10.1021/jo070560h
Kadir NHA, Salleh WMNHW, Ghani NA. (2022). A systematic review on essential oils and biological activities of the genus Syzygium (Myrtaceae). Rivista Italiana Delle Sostanze Grasse, 99(2), 165-178.
Khamidova UB., Terenteva EO, Azimova ShS. (2021). Isolation of skin fibroblasts by new modified method. Uzbek Biological Journal, 5, 7-10.
Kim AN, Ngamnithiporn A, Du E, Stoltz BM. (2023). Recent advances in the total synthesis of the tetrahydroisoquinoline alkaloids (2002–2020). Chemical Reviews, 123, 9447-9496. doi:10.1021/acs.chemrev.3c00054
Kolotova NV, Starkova AV, Gashina SV. (2016). Synthesis and biological activity of monosubstituted hydrazides of itaconic and dimethylmaleic acids. Issues of Ensuring the Quality of Medicines, 3(13), 15-23.
Larghi EL, Bohn ML, Kaufman TS. (2009). Aaptamine and related products: Their isolation, chemical syntheses, and biological activity. Tetrahedron, 65(22), 4257-4282. doi:10.1016/j.tet.2009.03.027
Ma K, Zhou P, Zhang W, Zeng L, Tao K, Zhang P. (2025). Itaconic acid: a regulator of immune responses and inflammatory metabolism. Current Issues in Molecular Biology, 47(7), 534. doi:10.3390/cimb47070534
Malikova RN, Sakhautdinov IM, Terenteva EO, Khashimova ZS, Yunusov MS, Azimova ShS. (2020). Synthesis and cytotoxic activity of a series of functionalized maleopimarimides. Chemistry of Natural Compounds, 56, 101-104 doi:10.1007/s10600-020-02953-z
Mao Ya, Soni K, Sangani Ch , Yao Y. (2020). An overview of privileged scaffold: Quinolines and isoquinolines in medicinal chemistry as anticancer agents. Current Topics in Medicinal Chemistry, 20(28), 2599-2633. doi:10.2174/1568026620999200917154225
Nehra B, Mathew B, Chawla PA. (2022). A medicinal chemist's perspective towards structure activity relationship of heterocycle based anticancer agents. Current Topics in Medicinal Chemistry, 22(6), 493-528. doi:10.2174/1568026622666220111142617
Niks M, Otto M. (1990). Towards an optimized MTT assay. Journal of Immunological Methods, 130, 149-151. doi: 10.1016/0022-1759(90)90309-j
Niyazmetov AR, Terent’eva EO, Khamidova UB, Khashimova ZS, Azimova ShS, Vinogradova VI. (2020). Synthesis of derivatives of the 2-arylquinoline alkaloid dubamine and their cytotoxicity. Chemistry of Natural Compounds, 56, 511-517. doi:10.1007/s10600-020-03074-3
Perkovic I, Beus M, Schols D, Persoons L, Zorc B. (2020). Itaconic acid hybrids as potential anticancer agents. Molecular Diversity, 26(1), 1-14. doi:10.1007/s11030-020-10147-6
Qing ZX, Huang JL, Yang XY, Liu JH, Cao HL, Xian F, Zeng JG. (2018). Anticancer and reversing multidrug resistance activities of natural isoquinoline alkaloids and their structure-activity relationship. Current Medicinal Chemistry, 25(38), 5088-5114. doi:10.2174/0929867324666170920125135
Reddy YD, Kumari YB, Dubey PK. (2013). Synthesis of a novel water soluble phthalimide derivative of acetaminophen as potential analgesic and antipyretic agent. Indian Journal of Chemistry, 52(39), 691-693. doi:10.1002/chin.201337061
Saidov AS, Turgunov KK, Levkovich MG, Vinogradova VI. (2015). Synthesis of bis-tetrahydroisoquinolines based on homoveratrylamine and several dibasic acids. 4. Reaction with malonic and succinic acids. Chemistry of Natural Compounds, 51, 316-319. doi:10.1007/s10600-015-1268-x
Saidov AS, Alimova M, Levkovich MG, Vinogradova VI. (2013). Synthesis of bis-tetrahydroisoquinolines based on homoveratrylamine and a series of dibasic acids. Chemistry of Natural Compounds, 49, 302-304. doi:10.1007/s10600-013-0586-0
Saidov ASh, Levkovich MG, Vinogradova VI. (2016). Interaction of homoveratrilamine with malic and fumaric acids. Chemistry for Sustainable Development, 24(6), 823-826.
Salleh WMNHW, Ahmad F, Khong HY. (2015). Chemical constituents from Piper caninum and antibacterial activity. Journal of Applied Pharmaceutical Science, 5(6), 20-25. doi:10.7324/JAPS.2015.50604
Salleh WMNHW, Hashim NA, Khamis S. (2019). Chemical constituents and lipoxygenase inhibitory activity of Piper stylosum MiQ. Bulletin of the Chemical Society of Ethiopia, 33(3), 587-592. doi:10.4314/bcse.v33i3.19
Sevior DK, Pelkonen O, Ahokas JT. (2012). Hepatocytes: the powerhouse of biotransformation. The International Journal of Biochemistry & Cell Biology, 44(2), 257-261. doi: 10.1016/j.biocel.2011.11.011
Shakri NM, Salleh WMNHW, Khamis S, Ali NAM, Shaharudin SM. (2020). Chemical composition of the essential oils of four Polyalthia species from Malaysia. Zeitschrift für Naturforschung C A Journal of Biosciences, 75(11-12), 473-478. doi:10.1515/znc-2020-0097
Shukla KH, Boehmler DJ, Bogacyzk S, Duvall BR, Peterson WA, McElroy WT, DeShong P. (2006). Application of palladium-catalyzed allylic arylation to the synthesis of a (±)-7-deoxypancratistatin analogue. Organic Letters, 8, 4183-4186. doi:10.1021/ol061070z
Stubbs NM, Roady TJ, Schwermann MP, Eteshola EO, MacDonald WJ, Purcell C, Ryspayeva D, Verovkina N, Tajiknia V, Ghandali M, Voong V, Lannigan AJ, Raufi AG , Lawler S, Holder SL, Carneiro BA, Cheng L, Safran HP, Graff SL, Dizon DS, Mani SA, Seyhan AA, Sobol RW, Wong ET, Chen CC, Gokaslan Z, Taylor MS, Rivers BM, El-Deiry WS. (2025). Acquired resistance to molecularly targeted therapies for cancer. Cancer Drug Resistance, 8, 27. doi:10.20517/cdr.2024.189
Terenteva EO, Khashimova ZS, Tsay EA, Jurakulov ShN, Saidov ASh, Vinogradova VI, Azimova ShS. (2017). Chemical modification of tetrahydroisoquinolines and their cytotoxic activity. Asian Journal of Pharmacy and Pharmacology, 3(3), 66-78.
Tseomashko NE, Terent’eva EO, Kodirova DB, Okhunov II, Aripova SF, Khashimova ZS, Azimova ShS. (2013) Synthesis of convolinine and cytotoxic activity of alkaloids of the genus Convolvulus and their derivatives. Chemistry of Natural Compounds, 48, 1039-1041. doi:10.1007/s10600-013-0459-6
Tukhtaev DB, Yusupov AB, Vinogradova VI. (2021). Synthesis of new amides based on N-phthaloyl-α-amino acids. Egyptian Journal of Chemistry, 64, 3049-3058 doi:10.21608/ejchem.2021.48494.2990
Zhurakulov SN, Mamadalieva NZ, Vinogradova VI, Mollica A, Procino E, Turgunov KK, Umarova MR, Terenteva EO, Azimova ShS. (2025). Design and synthesis of cryptostyline I derivatives: Cytotoxic activity and molecular docking insights. ChemistrySelect, 10, e01526, 1-15. doi.org/10.1002/slct.202501526
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Mukaddas Umarova Umarova , Ekaterina Terenteva, Ziroat Urunbaeva, Umida Khamidova, Elvira Yusupova, Valentina Vinogradova, Abdusalom Saidov, Shakhnoz Azimova
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
