C5-curcuminoid-4-aminoquinoline based molecular hybrids: Design, synthesis and mechanistic investigation of anticancer activity
Shamseer Kulangara Kandi,a Sunny Manohar,a Christian E. Vélez Gerena,bBeatriz Zayas,b Sanjay V.Malhotrac* and Diwan S. Rawata*
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Abstract: Theprivileged scaffolds of curcumin and 4-aminoquinolines are extensively used in the design and synthesis of biodynamic agents having remarkable efficacy against diseases like cancer and malaria. Therefore, we anticipated that covalent hybridization of these two pharmacophoreviatriazole linker may lead to molecules with better anticancer activity. The synthesized hybrid compounds were tested …show more content…
About 70% cancer related deaths are mainly due to lung, stomach, liver, colon and breast cancers. , It is well established that there is no single treatment of cancer and patients often receive a combination of therapies and palliative care, such as surgery, radiation, chemotherapy, immunotherapy, hormone therapy or gene therapy depending on the type and stage of the cancer, age, health status, and additional personal characteristics. Anticancer drugs such as alkylating agents, - antimetabolites, - plant alkaloids, - topoisomerase inhibitors , and cytotoxic antibiotics have been used extensively in cancer chemotherapy. Among these, natural products hold good promises in the development of anticancer molecules , and curcumin is one such class of compounds which has been extensively studied over the past few decades. These studies revealed that curcumin shows anticancer activity against prostate cancer, cervical cancer, colorectal carcinoma, leukemia and human breast cancer cells. In spite of huge medicinal potential, clinical use of curcumin has been hampered due to its poor solubility, bioavailability and absorption as well as rapid metabolism. - The pharmacokinetic studies demonstrate that the β-diketone functionality of curcumin is a substrate for liver aldoketo reductases and this may be one of the …show more content…
Subsequently, the mesylated products (3a-b) were converted into corresponding azides (4a-b) using sodium azide as nucleophile and DMF as solvent at 50 oC. These azides (4a-b) were reacted with 1-(prop-2-yn-1-yl)piperidin-4-one (5) by click chemistry using standard protocols of sodium ascorbate and copper sulfate as catalyst and an equimolar ratio of water and t-butanol as solvents to yield 1,2,3-triazole linker contained intermediates (6a-b). In the final step, the intermediates (6a-b) were subjected to aldol condensation with substituted benzaldehydes in the presence of 20% aqueous NaOH solution in ethanol to get the final targeted products (7a-g and 8a-g). It may be noted that, the intermediate compound 1-(prop-2-yn-1-yl)piperidin-4-one (5) was synthesized via nucleophilic substitution reaction between 4-piperidone hydrochloride monohydrate and propargyl bromide in the presence of anhydrous K2CO3 in the biphasic system [CHCl3:H2O (1:1)] at room temperature in good
Shamseer Kulangara Kandi,a Sunny Manohar,a Christian E. Vélez Gerena,bBeatriz Zayas,b Sanjay V.Malhotrac* and Diwan S. Rawata*
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Abstract: Theprivileged scaffolds of curcumin and 4-aminoquinolines are extensively used in the design and synthesis of biodynamic agents having remarkable efficacy against diseases like cancer and malaria. Therefore, we anticipated that covalent hybridization of these two pharmacophoreviatriazole linker may lead to molecules with better anticancer activity. The synthesized hybrid compounds were tested …show more content…
About 70% cancer related deaths are mainly due to lung, stomach, liver, colon and breast cancers. , It is well established that there is no single treatment of cancer and patients often receive a combination of therapies and palliative care, such as surgery, radiation, chemotherapy, immunotherapy, hormone therapy or gene therapy depending on the type and stage of the cancer, age, health status, and additional personal characteristics. Anticancer drugs such as alkylating agents, - antimetabolites, - plant alkaloids, - topoisomerase inhibitors , and cytotoxic antibiotics have been used extensively in cancer chemotherapy. Among these, natural products hold good promises in the development of anticancer molecules , and curcumin is one such class of compounds which has been extensively studied over the past few decades. These studies revealed that curcumin shows anticancer activity against prostate cancer, cervical cancer, colorectal carcinoma, leukemia and human breast cancer cells. In spite of huge medicinal potential, clinical use of curcumin has been hampered due to its poor solubility, bioavailability and absorption as well as rapid metabolism. - The pharmacokinetic studies demonstrate that the β-diketone functionality of curcumin is a substrate for liver aldoketo reductases and this may be one of the …show more content…
Subsequently, the mesylated products (3a-b) were converted into corresponding azides (4a-b) using sodium azide as nucleophile and DMF as solvent at 50 oC. These azides (4a-b) were reacted with 1-(prop-2-yn-1-yl)piperidin-4-one (5) by click chemistry using standard protocols of sodium ascorbate and copper sulfate as catalyst and an equimolar ratio of water and t-butanol as solvents to yield 1,2,3-triazole linker contained intermediates (6a-b). In the final step, the intermediates (6a-b) were subjected to aldol condensation with substituted benzaldehydes in the presence of 20% aqueous NaOH solution in ethanol to get the final targeted products (7a-g and 8a-g). It may be noted that, the intermediate compound 1-(prop-2-yn-1-yl)piperidin-4-one (5) was synthesized via nucleophilic substitution reaction between 4-piperidone hydrochloride monohydrate and propargyl bromide in the presence of anhydrous K2CO3 in the biphasic system [CHCl3:H2O (1:1)] at room temperature in good