Synthesis of some novel hydrazide-hydrazones derived from etodolac as potential anti-prostate cancer agents

Hande Cevher Koç; İrem Atlıhan; Pınar Mega Tiber; Oya Orun; Ş.güniz Küçükgüzel

Synthesis of some novel hydrazide-hydrazones derived from etodolac as potential anti-prostate cancer agents

Abstract

(R,S)-Etodolac [1,8-diethyl-1,3,4,9-tetrahydrapyrano(3,4-b)indole-1-acetic acid] is a nonsteroidal antiinflammatory drug that contains carboxylic acid group with the structure of pyrano[3,4-b]indole. In this study, a series of novel (R,S)-Etodolac derivatives (3a-l) bearing hydrazide-hydrazone moiety were synthesized. The structures of these compounds were characterized by spectral (1H-NMR and FT-IR analyses) methods. All synthesized compounds were screened for anticancer activity against androgen-independent prostate adenocarcinoma (PC-3, DU-145) and androgen-dependent prostate adenocarcinoma (LNCaP) cell lines by using WST-8 colorimetric method. This method was used for cell viability and cytotoxicity analysis. Compound 3b (SGK-720) [2-(1,8-diethyl-1,3,4,9tetrahydropyrano[3,4-b]indole-1-yl)acetic acid[(2,6-dichlorophenyl)methylene]hydrazides] showed 10.36, 5.24, 15.53 µM anticancer activity against PC3, DU145, LNCaP cancer cell lines, respectively. According to JC-1 mitochondrial membrane potential test and Annexin V/PI staining, 3b was found to have apoptotic effect on these cancer cells. It is concluded that compound 3b containing 2,6-dichloro substituents may be one of the candidate molecules to cope with prostate cancer.

Keywords

References

[1] Kamijo T, Sato T, Nagatomi Y, Kitamura T. Induction of apoptosis by cyclooxygenase-2 inhibitors in prostate cancer cell lines. Int J Urol. 2001; 8(7): 35-39. [CrossRef]
[2] Shigemura K, Shirakawa T, Wada Y, Kamidono S, Fujisawa M, Gotoh A. Antitumor effects of etodolac, a selective cyclooxygenase-2 inhibitor, against human prostate cancer cell lines in vitro and in vivo. Urology. 2005; 66(6): 12391244. [CrossRef]
[3] Okamoto A, Shirakawa T, Bito T, Shigemura K, Hamada K, Gotoh A, Fujisawa M, Kawabata M. Etodolac, a selective cyclooxygenase-2 inhibitor, induces upregulation of e-cadherin and has antitumor effect on human bladder cancer cells in vitro and in vivo. Urology. 2008; 71(1): 156-160. [CrossRef]
[4] Çıkla P, Özsavcı D, Bingöl-Özakpınar Ö, Şener A, Çevik Ö, Özbaş-Turan S, Akbuğa J, Şahin F, Küçükgüzel ŞG. Synthesis, cytotoxicity, and pro-apoptosis activity of etodolac hydrazide derivatives as anticancer agents. Arch Pharm (Weinheim). 2013; 346(5): 367-379. [CrossRef]
[5] Çıkla-Süzgün P, Kaushik-Basu N, Basu A, Arora P, Talele TT, Durmaz I, Cetin-Atalay R, Kucukguzel SG. Anti-cancer and anti-hepatitis C virus NS5B polymerase activity of etodolac 1,2,4-triazoles. J Enzyme Inhib Med Chem. 2015; 30(5): 778-785. [CrossRef]
[6] Çoruh I, Çevik Ö, Yelekçi K, Djikic T, Küçükgüzel ŞG. Synthesis, anticancer activity, and molecular modeling of etodolac-thioether derivatives as potent methionine aminopeptidase (type II) inhibitors. Arch Pharm (Weinheim). 2018; 351(3-4): e1700195. [CrossRef]
[7] Rollas S, Küçükgüzel ŞG. Biological activities of hydrazone derivatives. Molecules. 2007; 12: 1910-1939. [CrossRef]
[8] Kömürcü ŞG, Rollas S, Ülgen M, Gorrod JW, Çevikbaş A. Evaluation of some arylhydrazones of p-aminobenzoic acid hydrazide as antimicrobial agents and their in-vitro hepatic microsomal metabolism. Boll Chim Farm. 1995; 134(7): 375-379.

[9] Koçyiğit-Kaymakçıoğlu B, Ünsalan S, Küçükgüzel ŞG, Şener G, Rollas S. HPLC analysis of in vivo metabolites of 4nitrobenzoic acid [(5-nitro-2-thiophenyl)methylene]hydrazide in rats. Eur J Drug Metab Pharmacokinet. 2007; 32(4): 197-203. [CrossRef]
[10] Rollas S, Küçükgüzel ŞG. Hydrazone, amide, carbamate, macromolecular and other prodrugs of doxorubicin. Open Drug Deliv J. 2008; 2: 77-85. [CrossRef]
[11] Aydın S, Kaushik-Basu N, Arora P, Basu A, Nichols DB, Talele TT, Akkurt M, Çelik İ, Büyükgüngör O, Küçükgüzel ŞG. Microwave assisted synthesis of some novel flurbiprofen hydrazide-hydrazones as anti-HCV NS5B and anticancer agents. Marmara Pharm J. 2013; 17: 181-189. [CrossRef]
[12] Küçükgüzel ŞG, Koç D, Çıkla-Süzgün P, Özsavcı D, Bingöl-Özakpınar Ö, Mega-Tiber P, Orun O, Erzincan P, SağErdem S, Şahin F. Synthesis of tolmetin hydrazide-hydrazones and discovery of a potent apoptosis inducer in colon cancer cells. Arch Pharm (Weinheim). 2015; 348(10): 730-742. [CrossRef]
[13] Şenkardeş S, Kaushik-Basu N, Durmaz İ, Manvar D, Basu A, Atalay R, Küçükgüzel ŞG. Synthesis of novel diflunisal hydrazide-hydrazones as anti-hepatitis C virus agent and hepatocellular carcinoma inhibitors. Eur J Med Chem. 2016; 108: 301-308. [CrossRef]
[14] Çıkla-Süzgün P, Küçükgüzel ŞG. Recent advances in apoptosis: the role of hydrazones. Mini Rev Med Chem. 2019; 19(17): 1427-1442. [CrossRef]
[15] Han Mİ, Bekçi H, Uba Aİ, Yıldırım Y, Karasulu E, Cumaoğlu A, Karasulu HY, Yelekçi K, Yılmaz Ö, Küçükgüzel ŞG.Synthesis, molecular modeling, in vivo study, and anticancer activity of 1,2,4-triazole containing hydrazidehydrazones derived from (S)-naproxen. Arch Pharm (Weinheim). 2019; 352(6): e1800365. [CrossRef]
[16] Han Mİ, Atalay P, İmamoğlu N, Küçükgüzel ŞG. Synthesis, characterization and anticancer activity of novel hydrazide-hydrazones derived from ethyl paraben. J Res Pharm. 2020; 24(3): 341-349. [CrossRef]
[17] Şenkardeş S, Türe A, Ekrek S, Durak AT, Abbak M, Çevik Ö, Kaşkatepe B, Küçükgüzel İ, Küçükgüzel ŞG. Novel 2,6disubstituted pyridine hydrazones: synthesis, anticancer activity, docking studies and effects on caspase-3-mediated apoptosis. J Mol Struct. 2021; 1223: 128962. [CrossRef]
[18] Han Mİ, Atalay P, Tunç CÜ, Ünal G, Dayan S, Aydın Ö, Küçükgüzel ŞG. Design and synthesis of novel (S)-naproxen hydrazide-hydrazones as potent VEGFR-2 inhibitors and their evaluation in vitro/in vivo breast cancer models. Bioorg Med Chem. 2021; 37: 116097. [CrossRef]
[19] Rutavichyus A, Valiulene S, Kuodis Z. Isomerism of hydrazones of (2-benzothiazolylthio)- and (2benzoxazolylthio)acetic acids. Chem Heterocycl Comp. 1995; 31(5): 629-633. [CrossRef]
[20] Rutavichyus A, Valiulene S, Kuodis Z. Synthesis and structure of hydrazones obtained from hydrazides of [5-(4pyridyl)-1,3,4-oxadiazol-2-ylthio]acetic or 2-[5-(4-pyridyl)-1,3,4-oxadiazol-2-ylthio]propionic acids. Chem Heterocycl Comp. 2000; 36(7): 851-856. [CrossRef]
[21] Çıkla P, Tatar E, Küçükgüzel İ, Şahin F, Yurdakul D, Basu A, Krishnan R, Nichols DB, Kaushik-Basu N, Küçükgüzel ŞG. Synthesis and characterization of flurbiprofen hydrazide derivatives as potential anti-HCV, anticancer and antimicrobial agents. Med Chem Res. 2013; 22: 5685-5699. [CrossRef]
[22] Vincenzo G, Franco P. 3-(2-trialkylsilyloxy)ethyl-7-ethyl-1H-indoles and method for their preparation. US 5,599,946. 1997.
[23] Raghavan BV, Ramana KV, Khera B, Kumar N. Process for the preparation of 1,8-disubstituted-1,3,4,9tetrahydropyrano (3,4-b)-indole-1-acetic acid esters. US 6,331,638 B1. 2001.

Details

Primary Language

English

Subjects

Pharmaceutical Chemistry

Journal Section

Research Article

Authors

Hande Cevher Koç ^* This is me
Türkiye

İrem Atlıhan
Türkiye

Pınar Mega Tiber This is me
Türkiye

Oya Orun
Türkiye

Ş.güniz Küçükgüzel
Türkiye

Publication Date

June 28, 2025

Submission Date

August 29, 2021

Acceptance Date

November 18, 2021

Published in Issue

Year 2022 Volume: 26 Number: 1

IZ

https://izlik.org/JA23BT87BE

Cite

RIS / Bibtex

APA

Cevher Koç, H., Atlıhan, İ., Mega Tiber, P., Orun, O., & Küçükgüzel, Ş. (2025). Synthesis of some novel hydrazide-hydrazones derived from etodolac as potential anti-prostate cancer agents. Journal of Research in Pharmacy, 26(1), 1-12. https://izlik.org/JA23BT87BE

AMA

1.Cevher Koç H, Atlıhan İ, Mega Tiber P, Orun O, Küçükgüzel Ş. Synthesis of some novel hydrazide-hydrazones derived from etodolac as potential anti-prostate cancer agents. J. Res. Pharm. 2025;26(1):1-12. https://izlik.org/JA23BT87BE

Chicago

Cevher Koç, Hande, İrem Atlıhan, Pınar Mega Tiber, Oya Orun, and Ş.güniz Küçükgüzel. 2025. “Synthesis of Some Novel Hydrazide-Hydrazones Derived from Etodolac As Potential Anti-Prostate Cancer Agents”. Journal of Research in Pharmacy 26 (1): 1-12. https://izlik.org/JA23BT87BE.

EndNote

Cevher Koç H, Atlıhan İ, Mega Tiber P, Orun O, Küçükgüzel Ş (June 1, 2025) Synthesis of some novel hydrazide-hydrazones derived from etodolac as potential anti-prostate cancer agents. Journal of Research in Pharmacy 26 1 1–12.

IEEE

[1]H. Cevher Koç, İ. Atlıhan, P. Mega Tiber, O. Orun, and Ş. Küçükgüzel, “Synthesis of some novel hydrazide-hydrazones derived from etodolac as potential anti-prostate cancer agents”, J. Res. Pharm., vol. 26, no. 1, pp. 1–12, June 2025, [Online]. Available: https://izlik.org/JA23BT87BE

ISNAD

Cevher Koç, Hande - Atlıhan, İrem - Mega Tiber, Pınar - Orun, Oya - Küçükgüzel, Ş.güniz. “Synthesis of Some Novel Hydrazide-Hydrazones Derived from Etodolac As Potential Anti-Prostate Cancer Agents”. Journal of Research in Pharmacy 26/1 (June 1, 2025): 1-12. https://izlik.org/JA23BT87BE.

JAMA

1.Cevher Koç H, Atlıhan İ, Mega Tiber P, Orun O, Küçükgüzel Ş. Synthesis of some novel hydrazide-hydrazones derived from etodolac as potential anti-prostate cancer agents. J. Res. Pharm. 2025;26:1–12.

MLA

Cevher Koç, Hande, et al. “Synthesis of Some Novel Hydrazide-Hydrazones Derived from Etodolac As Potential Anti-Prostate Cancer Agents”. Journal of Research in Pharmacy, vol. 26, no. 1, June 2025, pp. 1-12, https://izlik.org/JA23BT87BE.

Vancouver

1.Hande Cevher Koç, İrem Atlıhan, Pınar Mega Tiber, Oya Orun, Ş.güniz Küçükgüzel. Synthesis of some novel hydrazide-hydrazones derived from etodolac as potential anti-prostate cancer agents. J. Res. Pharm. [Internet]. 2025 Jun. 1;26(1):1-12. Available from: https://izlik.org/JA23BT87BE