Research Articles

2017  |  Vol: 3(3)  |  Issue: 3(May-June)
Chemical Modification of Tetrahydroisoquinolines and their Cytotoxic Activity

Еkaterina О. Тerentevaa*Zaynat SKhashimovab, Еlena АTsayaSherzod NZhurakulova, Аbdusalom ShSaidovcValentina IVinogradovaaShakhnoz SAzimovaa

aInstitute of the Chemistry of Plant Substances, Uzbek Academy of Sciences, M. Ulugbek str. 77, 100170 Tashkent, Uzbekistan; 

bInstitute of the Bioorganic Chemistry, Uzbek Academy of Sciences, M. Ulugbek str. 83, 100125 Tashkent, Uzbekistan; 

cSamarkand State University, Str. University Boulevard, 15, 140104 Samarkand, Uzbekistan.

*Corresponding author

Еkaterina О. Тerenteva

Institute of the Chemistry of Plant Substances, Uzbek Academy of Sciences, M. Ulugbek str. 77, 100170 Tashkent, Uzbekistan



Objective: The wide variety of potent biological activities of natural and synthetic isoquinoline alkaloids encouraged us to develop novel cytotoxic isoquinoline compounds. A variety of differently functionalized 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines were synthesized. Materials and methods: We employed classic intramolecular Bischler-Napieralski cyclodehydration to generate the isoquinoline core. All the structures were characterized by nuclear magnetic resonance and mass spectrometry. The cytotoxic activities against three human cancer cell lines and primary culture of healthy hepatocyte cells were evaluated for all the synthesized compounds and structure-activity relationships were established by MTT asay. Results: It was shown that 8a has demonstrated selective cytotoxicity against breast adenocarcinoma (IC50: 43.3 µM), 4d, 3f against laryngeal adenocarcinoma (IC50: 18.0 and 2.3 µM respectively) with the absence of toxicity to healthy cells. Bis compounds exhibit greater cytotoxic effect than mono-series compounds. Among bis samples 8f showed the greatest cytotoxic properties with an IC50 value of 3.1-4.0 µM. The all conjugate compounds completely lacked cytotoxicity toward cancer cell lines in this study. 10 b,d demonstrated proliferative activity. Conclusions: Thus, the most promising compounds for further study in vitro and in vivo methods are dibasic compound 8d, 8e. Later these substances can be offered as a basis for drugs with anti-tumor properties.

Keywords: 1,2,3,4-tetrahydroisoquinoline derivatives, Bischler-Napieralski cyclization, cancer cells, cytotoxicity


Abe K, Saitoh T, Horiguchi Y, Utsunomiya I, Taguchi K, 2005. Synthesis and neurotoxicity of tetrahydroisoquinoline derivatives for studying Parkinson's disease. Biological and Pharmaceutical Bulletin,  28: 1355-1362. 

Babkin VA, Ostroukhova NN, and Trofimova NN, 2011. Larch Biomass: From Chemical Composition to Innovative Products [in Russian], Novosibirsk Izdatelstvo Sibirskoe otdelenie Rossiyskoy Akademii Nauk, 236.

Cavell BE, Syed Alwi SS, Donlevy A, Packham G, 2011. Anti-angiogenic effects of dietary isothiocyanates: mechanisms of action and implications for human health. Biochemical Pharmacology,  81(3):327-336.

Debono AJ, Mistry SJ, Xie J, Muthiah D, Phillips J, Ventura S, Callaghan R, Pouton CW, Capuano B, Scammells PJ, 2014. The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents. ChemMedChem, 9(2):399-410.

Galán A, Moreno L, Párraga J, Serrano Á, Sanz MJ., Cortes D, Cabedo N, 2014. Novel isoquinoline derivatives as antimicrobial agents. Bioorganic & Medicinal Chemistry, 21(11):3221-3230.

Mihoubi M, Micale N, Scala A, Jarraya RM, Bouaziz A, Schirmeister T, Risitano F, Piperno A, Grassi G, 2015. Synthesis of C3/C1-Substituted Tetrahydroisoquinolines. Molecules, 20(8):14902-14914.

Mosmann T, 1983. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65:55–63.

Nifant’ev EE, Mosyurov SE, Kukhareva TS, Vasyanina LK, 2013. N,N´-diethyl-1,3-propanediamine in the dihydroquercetin aminomethylation reaction. Doklady Akademii Nauk, 451(4): 404–407.

Ott H, Hardtmann GE, Denzer M, Frey A J, Gogerty JH, Leslie GH, Trapold JH, 1968. Tetrahydroisoquino[2,1-d][1,4]benzodiazepines. Synthesis and neuropharmacological activity. Journal of Medicinal Chemistry, 11:777.

Patil R, Hosni-Ahmed A, Jones TS, Patil SA, Asres LB, Wang X, Yates RC, Geisert EE, Miller DD, 2014. Synthesis and in vitro evaluation of novel 1,2,3,4-tetrahydroisoquinoline derivatives as potent antiglioma agents. Anti-Cancer Agents in Medicinal Chemistry,   14(3):473-482.

Pingaew R, Mandi P, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V, 2014. Design, synthesis and molecular docking studies of novel N-benzenesulfonyl-1,2,3,4-tetrahydroisoquinoline-based triazoles with potential anticancer activity. European Journal of Medicinal Chemistry, 81:192-203.

Seo JW, Srisook E, Son HJ, Hwang O, Cha YN, Chi DY, 2008. Synthesis of tetrahydroisoquinoline derivatives that inhibit NO production in activated BV-2 microglial cells. European Journal of Medicinal Chemistry, 43: 1160-1170. 

Tseomashko NE, Tsay ЕA, Azimova ShS, 2015. Obtaining of the primary hepatocytes culture for in vitro research [in Russian]. Uzbek Biological Journal, 2: 40-42.

Uesawa Y, Mohri K, Kawase M, Ishihara M, Sakagami H, 2011. Quantitative structure-activity relationship (QSAR) analysis of tumor-specificity of 1,2,3,4-tetrahydroisoquinoline derivatives. Anticancer Research, 31(12):4231-4238.

Wang KR, Zhang BZ, Zhang W, Yan JX, Li J, Wang R,  2008. Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides, 29(6): 963-968.

Wanner KT, Beer H, Höfner G, Ludwig M, 1998. Asymmetric Synthesis and Enantioselectivity of Binding of 1-Aryl-1,2,3,4-Tetrahydroisoquinolines at the PCP Site of the NMDA-Receptor Complex. European Journal of Organic Chemistry, 2019-2029

Zhurakulov ShN, Levkovich MG, Vinogradova VI, 2014. Synthesis of Hydroxyethyl Perivatives of 1-aryltetrahydroisoquinoline alkaloids. Chemistry of Natural Compounds, 49: 1095-1098.

Zhurakulov ShN, Vinogradova VI, Levkovich MG, 2013. Synthesis of 1-aryltetrahydroisoquinoline alkaloids and their analogs. Chemistry of Natural Compounds, 49: 70-74.

Manuscript Management System
Submit Article Subscribe Most Popular Articles Join as Reviewer Email Alerts Open Access
Our Another Journal
Another Journal