A decade's overview of 2-aminothiophenes and their fused analogs as promising anticancer agents.

Over the past decades, cancer has been a challenging domain for medicinal chemists as it is an international health concern. In association, small molecules such as 2-aminothiophenes and their derivatives showed significant antitumor activity through variable modes of action. Therefore, this article aims to review the advances regarding these core scaffolds over the past 10 years, where 2-aminothiophenes and their fused analogs are classified and discussed according to their biological activity and mode of action, in the interest of boosting new design pathways for medicinal chemists to develop targeted antitumor candidates.

Discovery and optimization of 2,3-diaryl-1,3-thiazolidin-4-one-based derivatives as potent and selective cytotoxic agents with anti-inflammatory activity.

Several studies have indicated the potential therapeutic outcomes of combining selective COX-2 inhibitors with tubulin-targeting anticancer agents. In the current study, a novel series of thiazolidin-4-one-based derivatives (7a-q) was designed by merging the pharmacophoric features of some COXs inhibitors and tubulin polymerization inhibitors. Compounds 7a-q were synthesized and evaluated for their cytotoxic activity against MCF7, HT29, and A2780 cancer cell lines (IC50 = 0.02-17.02 µM). The cytotoxicity of 7a-q was also assessed against normal MRC5 cells (IC50 = 0.47-13.46 µM). Compounds 7c, 7i, and 7j, the most active in the MTT assay, significantly reduced the number of HT29 colonies compared to the control. Compounds 7c, 7i, and 7j also induced significant decreases in the tumor volumes and masses in Ehrlich solid carcinoma-bearing mice compared to the control. The three compounds also exhibited significant anti-HT29 migration activity in the wound-healing assay. They have also induced cell cycle arrest in HT29 cells at the S and G2/M phases. In addition, they induced significant increases in both early and late apoptotic events in HT29 cells compared to the control, where 7j showed the highest effect. On the other hand, compound 7j (1 µM) displayed weak inhibitory activity against tubulin polymerization compared to colchicine (3 µM). On the other hand, compounds 7a-q inhibited the activity of COX-2 (IC50 = 0.42-29.11 µM) compared to celecoxib (IC50 = 0.86 µM). In addition, 7c, 7i, and 7j showed moderate inhibition of inflammation in rats compared to indomethacin, with better GIT safety profiles. Molecular docking analysis revealed that 7c, 7i, and 7j have higher binding free energies towards COX-2 than COX-1. These above results suggested that 7j could serve as a potential anticancer drug candidate.

Metabolomic profile, anti-trypanosomal potential and molecular docking studies of Thunbergia grandifolia.

Trypanosomiasis is a protozoan disease transmitted via Trypanosoma brucei. This study aimed to examine the metabolic profile and anti-trypanosomal effect of methanol extract of Thunbergia grandifolia leaves. The liquid chromatography-high resolution electrospray ionisation mass spectrometry (LC-HRESIMS) revealed the identification of fifteen compounds of iridoid, flavonoid, lignan, phenolic acid, and alkaloid classes. The extract displayed a promising inhibitory activity against T. brucei TC 221 with MIC value of 1.90 µg/mL within 72 h. A subsequent in silico analysis of the dereplicated compounds (i.e. inverse docking, molecular dynamic simulation, and absolute binding free energy) suggested both rhodesain and farnesyl diphosphate synthase as probable targets for two compounds among those dereplicated ones in the plant extract (i.e. diphyllin and avacennone B). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling of diphyllin and avacennone were calculated accordingly, where both compounds showed acceptable drug-like properties. This study highlighted the antiparasitic potential of T. grandifolia leaves.

Annexin A2 (AnxA2) association with the clinicopathological data in different breast cancer subtypes: A possible role for AnxA2 in tumor heterogeneity and cancer progression.

BACKGROUND: Breast cancer is a highly heterogeneous type of neoplasia with molecular and biochemical alterations in the ductal epithelium. AnxA2 has a diverse functions and through intracellular interaction with other molecules promotes carcinogenesis. AIMS: To study the possible involvement of AnxA2 in breast cancer heterogeneity and cancer progression. PATIENTS AND METHODS: Tumor tissue and serum were obtained from different breast cancer subtypes. Tumor tissues were processed for histopathological studies. AnxA2 levels were assessed in the tissues by H scoring and in the serum by ELISA. AnxA2 levels were correlated with HER2 and Ki67 and with clinicopathological data. Normal breast tissues and serum from healthy subjects were used as controls. RESULTS: AnxA2 showed a peculiar distribution in tumor tissues and nearby interstitial tissues. Pattern of expressions varied in different subtypes with the highest expression in triple negative subtype. Tissue and serum AnxA2 showed significant co-upregulations in breast cancer. Moreover, they showed positive correlations with HER2 and Ki67 and associations with clinicopathological data including cancer staging and lymph node metastasis. CONCLUSION: For the best of our knowledge this is the first study showing correlation between AnxA2, the proposed prognostic marker and the well-established tumor markers; HER2 and Ki67. AnxA2 might contribute to breast cancer heterogeneity and is associated with poor prognosis. AnxA2 might be a prognostic marker and an additional marker for breast cancer grading and clinical staging. Interestingly, tissue and serum AnxA2 showed a strong correlation. Thus, assessing serum AnxA2 can be a noninvasive prognostic tool.

Novel 1,2,4-triazole derivatives as apoptotic inducers targeting p53: Synthesis and antiproliferative activity.

A series of novel thiazolo[3,2-b][1,2,4]-triazoles 3a-n has been synthesized and evaluated in vitro as potential antiproliferative. Compounds 3b-d exhibited significant antiproliferative activity. Compound 3b was the most potent with Mean GI50 1.37 µM comparing to doxorubicin (GI50 1.13 µM). The transcription effects of 3b, 3c and 3d on the p53 were assessed and compared with the reference doxorubicin. The results revealed an increase of 15-27 in p53 level compared to the test cells and that p53 protein level of 3b, 3c and 3d was significantly inductive (1419, 571 and 787 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL). The docking study of the new compounds 3a-n revealed high binding scores for the new compounds toward p53 binding domain in MDM2. The docking analyses revealed the highest affinities for compounds 3b-d which induced p53 activity in MCF-7 cancer cells. Compound 3b which exhibited the highest antiproliferative activity and induced the highest increase in p53 level in MCF-7 cells showed also the highest affinity to MDM2.

Design, Synthesis and Antiproliferative Evaluation of Novel 1,2,4-Triazole/Schiff Base Hybrids with EGFR and B-RAF Inhibitory Activities.

BACKGROUND: 1,2,4-triazoles possess a broad spectrum of biological activities such as analgesic, antimicrobial, antitubercular, anti-inflammatory and antineoplastic activities. This heterocycle and their derivatives were included into a wide variety of therapeutically interesting drugs. Hence, it is of great interest to explore new 1,2,4-triazoles as cytotoxic agents targeting EGFR, B-Raf kinases. METHODS: The final compounds 9a-b, 10a-b, 11a-b, 12a-b, 13a-b and 14a-f were prepared by refluxing a mixture of triazole 3a-b and 7a-d with the corresponding benzaldehyde derivatives 8a-d in absolute ethanol to afford the target final compounds in good yields. The newly synthesized triazole-containing compounds were assessed according to standard protocols for their in vitro antiproliferative activity against four human cancer cell lines including human pancreas cancer cell line (Panc-1), pancreatic carcinoma cells (PaCa-2), colon cancer cells (HT-29) and lung cancer cells (H-460) using the propidium iodide (PI) fluorescence assay. Compounds 9a and 13a were evaluated against EGFR, B-Raf and Tubulin anticancer targets. RESULTS: Compounds 9a, 9b, 10a, 11a, 12a, 13a and 13b showed remarkable antiproliferative activity against the tested cell lines with IC50 range of 1.3-5.9µM. Compounds 9a and 13a with the least IC50 values in the anticancer screening assay were tested against three known anticancer targets including EGFR, B-Raf kinase and Tubulin. The results revealed that compound 13a showed the highest potency against B-Raf and EGFR kinases with IC50 = 0.7 and 1.9 µM, respectively. CONCLUSION: 1,2,4-triazoles reported herein are potent EGFR, B-Raf inhibitors. These lead compounds will be subjected to more detailed mechanistic studies.

Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors.

A series of novel compounds carrying 1,2,4-triazole scaffold were prepared and evaluated for their antiproliferative activities against NCI 60 cell line. Compounds 10 (a, c), 11 (a-d), and 14 (a-e) were selected for evaluation at single concentration of 10 µM towards panel of sixty cancer cell lines. Some of nitric oxide (NO) donating triazole/oxime hybrids 11a-d showed antiproliferative activity better than their corresponding ketones. On the other hand, the thiazolo [3,2-b][1,2,4]-triazoles 14a-e showed remarkable antiproliferative activities against the same cell lines. Compound 14d was selected for five dose testing against the full panel of 60 human tumor cell lines. Compound 14d showed high selectivity against renal subpanel with selectivity ratio of 6.99 at GI50 level. Compounds 11a-d, 10a-d and 14a-e were tested against four cell lines using MTT assay then compounds of the least IC50 were evaluated against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compound 14d showed promising EGFR inhibitory activity of cancer cell proliferation and were also observed to be moderate BRAF and tubulin inhibitors. Moreover, cell cycle analysis and apoptosis assay were finished for compounds 14d and 14f. Finally molecular modeling studies were performed to explore the binding mode of the most active compounds to the target enzymes.

Novel 1,2,4-triazole derivatives as potential anticancer agents: Design, synthesis, molecular docking and mechanistic studies.

A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines using MTT assay. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g showed remarkable antiproliferative activity against the tested cell lines. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g with the least IC50 values in MTT assay were tested against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compounds 8c and 8d showed almost same BRAF inhibitory activity and were discovered to be potent inhibitors of cancer cell proliferation and were also observed to be strong Tubulin inhibitors. Moreover, 8c also showed the best EGFR inhibition with IC50 = 3.6 µM. Finally molecular modeling studies were performed to explore the binding mode of the most active compounds to the target enzymes.