2-(3-Aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides: A novel cluster of tumor-specific cytotoxins which reverse multidrug resistance

Abstract

A series of 2-(3-aryl-2-propenoyl)-3-methylquinoxaline-1,4-dioxides 3a-l were prepared by condensation of various aryl aldehydes with 2-acetyl-3-methylquinoxaline-1,4-dioxide 2. These compounds inhibit the growth of human Molt 4/C8 and CEM T-lymphocytes and the IC 50 values are mainly in the 5-30 μM range. The quinoxaline 1,4-dioxide 3j inhibited the growth of 58 human tumor cell lines, particularly leukemic and breast cancer neoplasms. All of the compounds 3a-l reversed the multidrug resistance (MDR) properties of murine L-5178Y leukemic cells which were transfected with the human MDR1 gene. The MDR-reversing effect may be due to the conjugated π-electron system forming a weak electron charge transfer complex with the Pglycoprotein-mediated efflux pump. The compounds in series 2 and 3 were assessed against HL-60, HSC-2, HSC-3 and HSC-4 malignant cells as well as HGF, HPC and HPLF normal cell lines which revealed that the majority of the compounds displayed a greater toxicity to neoplastic than normal cells. Various ways in which the project may be expanded are presented.

Transition metal complexes of thiosemicarbazones with quinoxaline hub: an emphasis on antidiabetic property

“…Quinoxaline derivatives have large applications in biochemistry and pharmacology as antimicrobial (Badran et al, 2003) antineoplastic agents and tumour-specific cytotoxins (Das et al, 2009) and have exhibited significant in vitro activities against the human melanoma cell line A375, 110 (Deleuze-Masquefa et al, 2009). Mayer and Taberner (2002) reported the utility of quinoxaline derivatives as blood glucose level reducing agents and insulinomimetic agent in mice.…”

E-2-[3-(3,4-Dichlorophenyl)-1-oxo-2-propenyl]-3-methylquinoxaline-1,4-dioxide: A lead antitubercular agent which alters mitochondrial respiration in rat liver

“…The question arises as to whether correlations exist between the potencies of 1a – j , l in the antitubercular bioassays and the IC 50 values in the cytotoxic screens which have been reported earlier [25]. Consequently linear and semilogarithmic plots were made between the IC 50 values of 1a – j , l towards M. tuberculosis and the IC 50 figures of these compounds towards human Molt 4/C8, CEM, HL-60, HSC-2, HSC-3 and HSC-4 cells.…”

“…Hence the lack of bioactivity of 1k does not appear due to any unique electronic, hydrophobic or steric properties of the 4-nitro group. One may also note that the potency of 1k towards six human neoplastic and transformed cell lines was invariably much lower than was displayed by 1a – j , l [25]. For example, while the average IC 50 values of 1a – j , l towards human Molt 4/C8 and CEM T-lymphocytes are 13.4 and 16.1 μM, respectively, the corresponding figures for 1k are 261 and 164 μM, respectively [25].…”

“…One may also note that the potency of 1k towards six human neoplastic and transformed cell lines was invariably much lower than was displayed by 1a – j , l [25]. For example, while the average IC 50 values of 1a – j , l towards human Molt 4/C8 and CEM T-lymphocytes are 13.4 and 16.1 μM, respectively, the corresponding figures for 1k are 261 and 164 μM, respectively [25]. Thus in regard to the bioassays undertaken to date, the insertion of a nitro group in the 4 position of ring A in series 1 has a deleterious effect on both antitubercular and antineoplastic properties.…”

“…This investigation assumes some importance in view of our recent disclosure that most of the compounds in series 1 have significant cytotoxic potencies towards a wide range of human tumour cell lines [25] which has been reported earlier. Consequently the potential for the future development of series 1 will be enhanced greatly should antitubercular properties be displayed by these compounds.…”