The Conjugates of Indolo[2,3-]quinoline As Anti-Pancreatic Cancer Agents: Design, Synthesis, Molecular Docking and Biological Evaluations

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Mar 13

PMID 38473820

Authors

Marcin Cybulski

Katarzyna Sidoryk

Magdalena Zaremba-Czogalla

Bartosz Trzaskowski

Marek Kubiszewski

Joanna Tobiasz

Anna Jaromin

Olga Michalak

Affiliations

Soon will be listed here.

Abstract

New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5-indolo[2,3-]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5-indolo[2,3-]quinoline (), which contains the ortho-coumaric acid fragment, demonstrated dose-dependent effectiveness against both normal BxPC-3 and metastatic AsPC-1 pancreatic cancer cells. The IC values for AsPC-1 and BxPC-3 were 336.5 nM and 347.5 nM, respectively, with a selectivity index of approximately 5 for both pancreatic cancer cells compared to normal dermal fibroblasts. Conjugate did not exhibit any hemolytic activity against human erythrocytes at the tested concentration. Computational studies were performed to predict the pharmacokinetic profile and potential mechanism of action of the synthesized conjugates. These studies focused on the ADME properties of the conjugates and their interactions with DNA, as well as DNA-topoisomerase alpha and beta complexes. All of the conjugates studied showed approximately one order of magnitude stronger binding to DNA compared to the reference DiMIQ, and approximately two orders of magnitude stronger binding to the topoisomerase II-DNA complex compared to DiMIQ. Conjugate was predicted to have the strongest binding to the enzyme-DNA complex, with a Ki value of 2.8 nM.

Citing Articles

The conjugates of 5'-deoxy-5-fluorocytidine and hydroxycinnamic acids - synthesis, anti-pancreatic cancer activity and molecular docking studies.

Cybulski M, Zaremba-Czogalla M, Trzaskowski B, Kubiszewski M, Tobiasz J, Jaromin A RSC Adv. 2024; 14(19):13129-13141.

PMID: 38655481 PMC: 11036175. DOI: 10.1039/d4ra01683a.

Special Issue "Development and Synthesis of Biologically Active Compounds".

Gazieva G, Chegaev K Int J Mol Sci. 2024; 25(7).

PMID: 38612824 PMC: 11012345. DOI: 10.3390/ijms25074015.

References

Quelever G, Burlet S, Garino C, Pietrancosta N, Laras Y, Kraus J . Simple coupling reaction between amino acids and weakly nucleophilic heteroaromatic amines. J Comb Chem. 2004; 6(5):695-8. DOI: 10.1021/cc034069p. View

Sidoryk K, Switalska M, Jaromin A, Cmoch P, Bujak I, Kaczmarska M . The synthesis of indolo[2,3-b]quinoline derivatives with a guanidine group: highly selective cytotoxic agents. Eur J Med Chem. 2015; 105:208-19. DOI: 10.1016/j.ejmech.2015.10.022. View

Kumar H, Herrmann L, Tsogoeva S . Structural hybridization as a facile approach to new drug candidates. Bioorg Med Chem Lett. 2020; 30(23):127514. DOI: 10.1016/j.bmcl.2020.127514. View

Kudo M . Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond. World J Gastroenterol. 2019; 25(7):789-807. PMC: 6385008. DOI: 10.3748/wjg.v25.i7.789. View

Bukowski N, Pandey J, Doyle L, Richard T, Anderson C, Zhu Y . Development of a clickable designer monolignol for interrogation of lignification in plant cell walls. Bioconjug Chem. 2014; 25(12):2189-96. DOI: 10.1021/bc500411u. View

Kayahan N, Karaca M, Satis H, Yapar D, Ozet A . Folfirinox versus gemcitabine-cisplatin combination as first-line therapy in treatment of pancreaticobiliary cancer. Turk J Med Sci. 2020; 51(4):1727-1732. PMC: 8569782. DOI: 10.3906/sag-2009-115. View

Wu C, Li T, Farh L, Lin L, Lin T, Yu Y . Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science. 2011; 333(6041):459-62. DOI: 10.1126/science.1204117. View

Lisgarten J, Coll M, Portugal J, Wright C, Aymami J . The antimalarial and cytotoxic drug cryptolepine intercalates into DNA at cytosine-cytosine sites. Nat Struct Biol. 2001; 9(1):57-60. DOI: 10.1038/nsb729. View

Rabiej-Koziol D, Krzeminski M, Szydlowska-Czerniak A . Synthesis of Steryl Hydroxycinnamates to Enhance Antioxidant Activity of Rapeseed Oil and Emulsions. Materials (Basel). 2020; 13(20). PMC: 7600874. DOI: 10.3390/ma13204536. View

10.

Wendorff T, Schmidt B, Heslop P, Austin C, Berger J . The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. J Mol Biol. 2012; 424(3-4):109-24. PMC: 3584591. DOI: 10.1016/j.jmb.2012.07.014. View

11.

Kamran S, Sinniah A, Chik Z, Alshawsh M . Diosmetin Exerts Synergistic Effects in Combination with 5-Fluorouracil in Colorectal Cancer Cells. Biomedicines. 2022; 10(3). PMC: 8945009. DOI: 10.3390/biomedicines10030531. View

12.

Zhang L, Xu Z . Coumarin-containing hybrids and their anticancer activities. Eur J Med Chem. 2019; 181:111587. DOI: 10.1016/j.ejmech.2019.111587. View

13.

Diyabalanage H, Granda M, Hooker J . Combination therapy: histone deacetylase inhibitors and platinum-based chemotherapeutics for cancer. Cancer Lett. 2012; 329(1):1-8. PMC: 3546543. DOI: 10.1016/j.canlet.2012.09.018. View

14.

Kleczkowska P, Kowalczyk A, Lesniak A, Bujalska-Zadrozny M . The Discovery and Development of Drug Combinations for the Treatment of Various Diseases from Patent Literature (1980-Present). Curr Top Med Chem. 2016; 17(8):875-894. DOI: 10.2174/1568026616666160818152257. View

15.

Zhang Q, Lu Q . New combination chemotherapy of cisplatin with an electron-donating compound for treatment of multiple cancers. Sci Rep. 2021; 11(1):788. PMC: 7804005. DOI: 10.1038/s41598-020-80876-z. View

16.

Granchi C, Fortunato S, Minutolo F . Anticancer agents interacting with membrane glucose transporters. Medchemcomm. 2017; 7(9):1716-1729. PMC: 5198910. DOI: 10.1039/C6MD00287K. View

17.

Sarwar T, Ishqi H, Rehman S, Husain M, Rahman Y, Tabish M . Caffeic acid binds to the minor groove of calf thymus DNA: A multi-spectroscopic, thermodynamics and molecular modelling study. Int J Biol Macromol. 2017; 98:319-328. DOI: 10.1016/j.ijbiomac.2017.02.014. View

18.

Lipinski C . Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2014; 1(4):337-41. DOI: 10.1016/j.ddtec.2004.11.007. View

19.

Calvaresi E, Hergenrother P . Glucose conjugation for the specific targeting and treatment of cancer. Chem Sci. 2013; 4(6):2319-2333. PMC: 3784344. DOI: 10.1039/C3SC22205E. View

20.

Canals A, Purciolas M, Aymami J, Coll M . The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs. Acta Crystallogr D Biol Crystallogr. 2005; 61(Pt 7):1009-12. DOI: 10.1107/S0907444905015404. View