Antiproliferative and Antiprostate Cancer Activities of Heterocyclic Compounds Derived from Cyclohexane-1,4-dione.

2-Amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) was prepared from the reaction of cyclohexane-1,4-dione with elemental sulfur and malononitrile in 1,4-dioxane and triethylamine as catalyst. The latter compound reacted with triethyl orthoformate and either malononitrile or ethyl cyanoacetate in 1,4-dioxane in the presence of triethylamine to produce 4H-thieno[2,3-f]chromene derivatives 10a,b. In addition, fused pyran and pyridine derivatives were synthesized starting from compound 3. The cytotoxicity of the synthesized compounds was studied on six cancer cell lines together with c-Met kinase and PC-3 cell line. The most active compounds were tested against five tyrosine kinases and Pim-1 kinase, most of which showed strong inhibition, encouraging further work.

Anti-proliferative, c-Met Inhibitions, and PAINS Evaluations of New Thiophene, Thiazole, Coumarin, Pyran, and Pyridine Derivatives.

BACKGROUND: 1,3-Diones are versatile reagents used for many heterocyclic transformations. Among such groups of compounds, cyclohexane-1,3-dione is widely used in organic synthesis to produce biologically active compounds. OBJECTIVE: In this work, target molecules were synthesized from tetrahydrobenzo[b]thiophen-3- carboxamide derivative with different substituents, and their structure-activity relationships were discussed in detail. METHODS: Cyclohexane-1,3-dione underwent different multi-component reactions to produce fused thiophene, thiazole, coumarin, pyran, and pyridine derivatives. The anti-proliferative activity of the newly synthesized compounds toward the six cancer cell lines, namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions of the most active compounds toward cancer cell lines classified according to the disease were also studied. Furthermore, Pan Assay Interference compounds (PAINS) of the selected compounds were analyzed, along with the c- Met inhibitions. RESULTS: Anti-proliferative evaluations were performed for all of the synthesized compounds, in which the varieties of substituents through the aryl ring and the heterocyclic ring afforded compounds with high activities. Inhibition activity against the cancer cell lines classified according to the disease, c-Met, and PAINS of the synthesized compounds were measured. CONCLUSION: Compounds 3, 13a, 13b, 14a, 16f, 17a, 28, 30a, and 31were the most cytotoxic compounds toward the six cancer cell lines. Inhibition toward cancer cell lines classified according to the disease showed that, in most cases, the presence of the electronegative CN and or Cl groups within the molecule was responsible for its high activity.

Heterocyclization of 2-Arylidenecyclohexan-1,3-dione: Synthesis of Thiophene, Thiazole, and Isoxazole Derivatives with Potential Antitumor Activities.

BACKGROUND: Thiophene, thiazole, and isoxazole derivatives are present in a wide range of natural and synthetic compounds with heterogeneous pharmacological activity. Due to their structural diversity, they are some of the most versatile classes of compounds for anticancer drug design and discovery. OBJECTIVE: Thiophene, thiazole, and isoxazole derivatives were herein designed with a dual purpose: as antiproliferative agents and kinase inhibitors. METHODS: The test compounds were synthesized in moderate to high yields through a simple methodology. Tetrahydrobenzo[b]thiophen-5-one derivatives 5a-f were prepared from the reaction of 2-arylidencyclohexan- 1,3-dione 3a-c with elemental sulfur and either of malononitrile (4a) or ethyl cyanoacetate (4b) in 1,4-dioxan in the presence of triethylamine. Compounds 5a,b were used for the synthesis of thiophene, thiazole, and isoxazole derivatives through their reactions with different chemical reagents. RESULTS: Antiproliferative evaluations, c-Met kinase, and Pim-1 kinase inhibitions were performed where some compounds revealed high activities. In all cases, antiproliferative activity and the kinase inhibitions were performed against six cancer cell lines and five tyrosine kinases, respectively. Where the most cytotoxic compounds were 3c, 5d, and 16c with IC50's 0.29, 0.68, and 0.42µM, respectively, against the A549 cell line. CONCLUSION: The anti-proliferative activities of the newly synthesized compounds were evaluated against the six cancer cell lines (A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460). The most potent compounds toward the cancer cell lines (3a, 3c, 5d, 7c, 11c, 16a, and 16c) were further investigated towards the five tyrosine kinases (c-kit, FIT-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5d, and 16c were selected for testing of their inhibition for the Pim-1 kinase due to their anti-proliferation activities against the cancer cell lines and their high activities against the tyrosine kinases.

New Approaches for the Uses of Cyclohexan-1,4-dione for the Synthesis of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridine Derivatives used as Potential Anti-prostate Cancer Agents and Pim-1 Kinase Inhibitors.

BACKGROUND: Among the wide range of heterocycles, tetrahydrobenzothienopyridine derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the thiophene nucleus were known in the market. METHOD: A series of tetrahydrobenzothienopyridine derivatives were synthesized from the reaction of 2-amino- 3-benzoyl-4,5-dihydrobenzo[b]thiophen-6(7H)-one, synthesized and used for further heterocyclization reactions through reaction with different reagents. RESULTS: Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed where some compounds revealed high activities. CONCLUSION: The inhibition of the newly synthesized compounds towards c-Met kinase, the five c-Metdependent cancer cell lines (A549, HT-29, MKN-45, U87MG, and SMMC-7721) and one c-Met-independent cancer cell line (H460) were investigated using foretinib as a standard drug. The results showed that compounds 6b, 7e, 9b, 9e, 16c and 20d were more active than foretinib. Furthermore, compounds 6b, 13b, 16b and 16c were selected to examine their Pim-1 kinase inhibition activity, where compounds 16b and 16c were of high potencies with IC50 values of 0.28 and 0.32 µM, while compounds 6b and 13b were less effective (IC50 > 10 µM).

Cytotoxicity and Anti-proliferative Properties of Heterocyclic Compounds Derived from Progesterone.

The following study explored the cytotoxic effect on human cancer cells of a series of novel progesterone derivatives through the synthesis of heterocyclic compounds incorporating progesterone moiety. The reaction of progesterone (1) with cyanoacetanilide derivatives gave the condensation products 3a,b. Either of compound 3a or 3b reacted with elemental sulfur affording the thiophene derivatives 4a and 4b, respectively. In addition, progesterone (1) underwent some multi-component reactions with aromatic aldehydes and cyanomethylene reagents in triethylamine to give the pyran derivatives 10a-f. Carrying the same reactions but using ammonium acetate afforded the pyridine derivatives 11a-f. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that nine compounds (3b, 7c, 10b, 10d, 10f, 11d, 13a, 13b and 14b) revealed optimal cytotoxic effect against cancer cell lines with IC50 ˂ 550 nM and their cytotoxicity's were higher than that of progesterone. Moreover, the toxicity of the most active compounds was measured against shrimp larvae. In addition, the anti-proliferative evaluations of these potent compounds were measured.