(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, 9-tetrahydropyrano [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.