Synthesis of Thiophene and NO-Curcuminoids for Antiinflammatory and Anti-Cancer Activities

Abstract

In search of better NSAIDs four novel nitric oxide donating derivatives of curcumin (compounds 9a–d), and four thiophene curcuminoids (compounds 10a–c, 11) have been synthesised. The cytotoxic effects of these compounds along with the lead compound curcumin (7) and their effect on the production of the reactive oxygen species nitric oxide and pro-inflammatory cytokines IL-1β, TNF-α and chemokine CXCL-8 were evaluated using human monocytic THP-1 and colon adenocarcinoma CACO-2 cell lines. All of the nitric oxide donating curcuminoids 9a–d and the thiophene curcuminoids 10a–c and 11 were non-cytotoxic to THP-1 cells over a concentration range of 10-100 μM and compared with curcumin compounds 10b and 10c, were more toxic. In CACO-2 cells, 10b and 11 appeared to be non-toxic at 10 to 50 μM, whereas 10a and 10c were non-cytotoxic at 10 μM only. These results clearly indicate that the introduction of a nitroxybutyl moiety to curcumin and replacement of phenyl rings with thiophene units reduces the cytotoxic effect of the parent curcumin, whereas a methyl substituted thiophene increases the cytotoxic effects. In THP-1 cells, drugs 10a and 11 significantly decreased IL-1-β production at their non-cytotoxic concentrations, whereas, they did not decrease TNF-α production in CACO-2 cells. Compound 11 showed a significant decrease in CXCL-8 production.

Modulators affecting the immune dialogue between human immune and colon cancer cells

“…These results were observed after co-culture of immune and cancer cells, indicating the likelihood of a direct interaction between immune and cancer cells, a plausible mechanism for explaining the inhibitory effect of curcumin on tumorigenesis. It is not wonder therefore, that efforts are ventured to synthesize compounds that are more efficient and less toxic than curcumin for augmentation the possibilities for colon cancer therapy [93] .…”

Preclinical screening of a novel compound, 2-chlorothiophene for analgesic activity in swiss albino mice

“…6,7,8 The LD50 values were estimated to be at more than 2g/kg which is far greater than the maximum testing dose in the current study. During this current study, 2-chlorothiophene was tested for analgesic activity at 10, 20 and 40mg/kg doses as the previous studies have proved that the parent compound has predominant analgesic activity at 15 to 30mg/kg.…”

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

“…3) was also used in the development of • NO donors. 87,88 Ahmed et al developed curcumin-based • NO donors 19a-d (Table 1) and their anticancer and anti-inflammatory activities were screened in human monocytic leukemia (THP-1) cells. Curcumin and derivatives 19a-d were not cytotoxic when incubated at 10 M and significantly increased nitrite production in the same cellular model.…”

“…Curcumin and derivatives 19a-d were not cytotoxic when incubated at 10 M and significantly increased nitrite production in the same cellular model. 87 The tetracyclic diterpenoid isosteviol ( Fig. 3) has attracted considerable interest due to its broad spectrum of biological activities, [89][90][91] and was thus used as scaffold for the development of • NO donors.…”