Abstract
In present investigation, an attempt was undertaken to modify the C-9 position of noscapine (Nos), an opium alkaloid to yield 9 -hydroxy methyl and 9 -carbaldehyde oxime analogues for augmenting anticancer potential. The synthesis of 9-hydroxy methyl analogue of Nos was carried out by Blanc reaction and 9-carbaldehyde oxime was engineered by oxime formation method and characterized using FT-IR, 1H NMR, 13C NMR, mass spectroscopy, and so on techniques. In silico docking techniques informed that 9-hydroxy methyl and 9-carbaldehyde oxime analogues of Nos had higher binding energy score as compared to Nos. The IC50 of Nos was estimated to be 46.8 µM signficantly (P < 0.05) higher than 8.2 µM of 9-carbaldehyde oxime and 4.6 µM of 9-hydroxy methyl analogue of Nos in U87, human glioblastoma cells. Moreover, there was significant (P < 0.05) difference between the IC50 of 9-carbaldehyde oxime and 9-hydroxy methyl analogue of Nos. Consistent to in vitro cytotoxicity data, 9-hydroxy methyl analogue of Nos induced significantly (P < 0.05) higher degree of apoptosis of 84.6% in U87 cells as compared to 78.5% and 64.3% demonstrated by 9-carbaldehyde oxime and Nos, respectively. Thus the higher therapeutic efficacy of 9-hydroxy methyl analogue of Nos may be credited to higher solubility and inhibitory constant (K).
Highlights
Most of the synthetic antineoplastic therapeutic modalities available today are immunosuppressive agents and exert several side-effects[1,2]
We have reported the anticancer activity and synthesis of several potent analogues of noscapine, a plant derived anticancer agent[9,10,11,12]
Structure-activity analysis demonstrated that modification of the proton at C-9 position of the isoquinoline ring in noscapine (Nos) can be done without affecting the tubulin binding
Summary
Most of the synthetic antineoplastic therapeutic modalities available today are immunosuppressive agents and exert several side-effects[1,2]. Noscapine is structurally and chemically different from other opium alkaloids such as morphine (Fig. 1), codeine, thebaine, papaverine and narceine It was used as anti-tussive agent but later on Ye and co-workers have discovered its anti-neoplastic properties in 1998. Structure-activity analysis demonstrated that modification of the proton at C-9 position of the isoquinoline ring in noscapine (Nos) can be done without affecting the tubulin binding activity. In this context, brominated (9-Br-Nos) and reduced brominated analogue of noscapine (Red-Br-Nos) exerted 5–40 folds more cytotoxicity as compared to parent compound, Nos in cancer cells[11,12]. The in vitro cytotoxicity[24] and apoptosis assays were utilized to examine the therapeutic potential of synthesized compounds against human glioblastoma cell line, U87 and U251 resistant glioblastoma cell line
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