Maintenance of telomeres – specialized complexes that protect the ends of chromosomes – is provided by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types. Telomeric ends of chromosomes consist of noncoding repeat sequences of guanine-rich DNA. These G-rich ends can fold into structures called G-quadruplexes. Stabilization of G-quadruplexes by small binding molecules called G4 ligands can prevent telomerase enzyme from maintaining telomere integrity in cancer cells. G-quadruplexes can exist in other parts of the genome too, especially within promoter sequences of oncogenes, and also be interesting drug targets. Here, we describe the development of a new series of novel bis-triazoles, designed to stabilize G-quadruplex structures selectively as G4 ligands. FRET assays showed two compounds to be moderately effective G4 binders, with particular affinity for the quadruplex formed by the Hsp90a promoter sequence, and good selectivity for G-quadruplex DNA vs. duplex DNA. However, CD spectroscopy failed to provide any information about the folding topology of the human telomeric G-quadruplex resulting from its interaction with one of the ligands. All the new ligands showed potent cell growth inhibitory properties against human colon and pancreatic cancer cell lines, as evidenced by the MTT assay; notably, they were more potent against cancer cells than in fetal lung fibroblasts. Docking studies were performed to rationalize the affinity of these ligands for binding to the telomeric parallel G-quadruplex DNA.

Background: The use of tyrosine kinase inhibitors (TKIs) as a treatment for CML has improved the natural history of the disease and increased the duration of survival. Tyrosine kinase inhibitors represent the success of target therapies that work on molecular targets, although some patients still have therapy failure. Vitamin D has anti-proliferative, pro-apoptotic, and anti-angiogenic effects on cells, therefore it can be considered as a potential cancer preventative and treatment agent. Inecalcitol (TX-522) is the14-epi-analogue of Calcitriol (1,25(OH)₂-vitamin D3), and inhibits cancer cell proliferation more effectively than Calcitriol. This study was conducted to evaluate the antiproliferative and synergistic effects of the anticancer drugs Imatinib and Dasatinib in combinations with Inecalcitol on human chronic myeloid leukemia K-562 cells. Method: The growth inhibitory activities of Inecalcitol, Imatinib, Dasatinib, and different combinations of one of the two drugs (Imatinib and Dasatinib) with Inecalcitol, were determined in vitro using MTT assay against K-562 cell line. Results: Inecalcitol, Imatinib, and Dasatinib showed potent antiproliferative activities against K-562 cells with GI₅₀ values of 5.6 µM, 0.327 µM, and 0.446 nM, respectively. Combinations of Imatinib or Dasatinib with different concentrations of Inecalcitol increased significantly the antiproliferative activities and potencies of both drugs (****p < 0.0001), with optimal GI₅₀ values of 580 pM (Imatinib) and 0.51 pM (Dasatinib). Conclusion: The study demonstrated that the human chronic myeloid leukemia K-562 cells were subjected to a synergistic growth inhibitory impact when antileukemic drugs (Imatinib or Dasatinib) were combined with Inecalcitol, therefore, it is recommended that these combinations be viewed as promising novel antileukemic medications and used in place of individual medications with lower dosages and negligible side effects in the treatment of CML.

Carboxamide derivatives are a promising class of compounds in anticancer drug discovery, owing to their ability to interact with multiple oncogenic targets and their favorable pharmacological profiles. In this study, we report the design, synthesis, and biological evaluation of a series of N-substituted 1H-indole-2-carboxamides as potential anticancer agents. The synthesized compounds were assessed for antiproliferative activity using the MTT assay against MCF-7 (breast cancer), K-562 (leukemia), and HCT-116 (colon cancer) cell lines, with normal human dermal fibroblasts included as a non-cancerous control. Several compounds demonstrated notable cytotoxicity and selectivity. Compounds 12, 14, and 4 exhibited potent activity against K-562 cells, with IC₅₀ values of 0.33 µM, 0.61 µM, and 0.61 µM, respectively. Compound 10 showed the most significant activity against HCT-116 cells (IC₅₀ = 1.01 µM) with a high selectivity index (SI = 99.4). Moderate cytotoxicity was observed against MCF-7 cells. To elucidate the mechanism of action, molecular docking and induced-fit docking studies were conducted against key cancer-related targets, including topoisomerase–DNA (PDB ID: 5ZRF), PI3Kα (4L23), and EGFR (3W32), revealing favorable binding interactions. Additionally, principal component analysis of molecular descriptors indicated that the compounds possess promising drug-like and lead-like properties, particularly compound 10. Overall, this study highlights N-substituted indole-2-carboxamides as promising scaffolds for further optimization. The integration of synthetic chemistry, biological assays, and computational modeling provides a robust foundation for the continued development of these compounds as potential anticancer agents.

Here, we describe further cytotoxic studies and reverse pharmacophore mapping (pharmacophore profiling) for bis-triazoles MS44-53, which were designed and synthesized previously to stabilize the G-quadruplex nucleic acids capable of being formed at the telomeric region and promoter sequences of genes involved in cellular proliferation and oncogenes. Pharmacophore-based activity profiling screen demonstrated some biological targets that MS44-53 may modulate their biological response, and thus can be considered as potential drugs to treat different kinds of diseases, such as carcinoma, diabetes type II, bacterial infection and cardiovascular diseases. Potent cell growth inhibitory properties were shown by ligands MS47 and MS49 against human melanoma MDA-MB-435, colon cancer HCT-116 and COLO 205, and pancreatic cancer MIA PaCa-2 cell lines, as evidenced by MTT assay. Both ligands were more potent against cancer cells than in skin normal CCD-1064Sk fibroblasts. Aim: The aim of this study is to identify the molecular target and mechanism of action of our promising anticancer bis-triazoles MS44-53, focusing specifically on the G-quadruplex stabilizers MS47 and MS49. Background: In molecular biology, G-quadruplexes (also known as G4-DNA), one of the higher-order structures of polynucleotides, are four stranded structures formed by nucleic acid sequences which are rich in guanine. They are formed mainly at the single-stranded G-overhang of telomeric DNA and within promoter sequences of genes involved in cellular proliferation and oncogenes such as c-myc, c-kit, and Hsp90. Stabilization of DNA G-quadruplexes is one of the anticancer strategies that has the potential to treat all cancers regardless of the type. A new series of bis-triazoles MS44-53 were developed to stabilize G-quadruplex structures selectively, as G4 ligands and experimental antitumour agents. FRET assay showed that MS47 and MS49 were only the best binders towards the Hsp90 promoter G-guadruplexes. While all bis-triazoles MS44-53 exhibited potent cell growth inhibitory activity against human carcinoma cell lines, suggesting that the ligands perturb molecular targets and mechanisms of action, other than stabilizing G-quadruplexes, contributing to antitumor activity. Therefore, the molecular targets and mechanisms of action of bis-triazoles MS44-53 in different types of human cancer cell lines should be determined by performing further computational studies to MS44-53 and in vitro evaluations for the G-quadruplex stabilizers MS47 and MS49. Objectives: 1- Determining the exact IC₅₀ for bis-triazoles MS47 & MS49 against four different types of human cancer cell lines; melanoma MDA-MB-435, pancreatic cancer MIA PaCa-2, and colon cancer HCT-116 and COLO 205 cell lines. 2- Predicting the biological targets that bis-triazoles MS44-53 may interact with to trigger or block their biological response. Methods: 1- MTT assay was used for in vitro evaluation of the antiproliferative activities of MS47 and MS49, and determination of IC₅₀ values. 2- Reverse pharmacophore mapping (pharmacophore profiling) was used for predicting the biological targets of bis-triazoles MS44-53, and determining the % binding probabilities. Results: MS49 exhibited more potent proliferation inhibitory activity than MS47 and higher IC₅₀ value against skin normal fibroblasts. Pharmacophore profiling demonstrated FGFR1, PDGFR2, FLT3, mTOR, PPAR-gamma, MUR-F and CETP as biological targets for bis-triazoles MS44-53. Conclusion: Bis-triazoles MS47 and MS49 are promising selective innovative compounds with wide spectrum cytotoxic activities against distinct cancer types. Bis-triazoles MS44-53 can be considered as potential drugs to treat different types of carcinoma, in addition to diabetes type II, bacterial infection and cardiovascular diseases. Other: Further in vitro evaluations will be performed for bis-triazoles MS44-53 in order to identify their molecular targets and mechanisms of action in different types of human cancer cell lines.

Topoisomerase II (Top-II) is an essential therapeutic target in cancer treatment owing to its overexpression in a wide variety of cancerous cells, including colorectal and breast cancer. Significant efforts have been made to discover and develop competitive inhibitors of the Top-II enzyme as potential anticancer agents. Herein, molecular modeling was employed to identify a new series of furyl-2-carboxamide derivatives as potential anticancer agents. Compounds 3, 5, and 7 were synthesized and characterized with the aid of several spectroscopic techniques, such as FT-IR, NMR, and mass spectroscopy, as well as elemental analysis. The anticancer activity properties of compounds 3, 5, and 7 were evaluated in vitro using an MTT assay in a human colorectal HCT-116 cell line with different concentration dilutions. The results indicate that the anthraquinone compound 3 is 1.3-1.6 times more potent against human colon cancer HCT-116 cells than the pyridine and benzophenone compounds 7 and 5, respectively, which reveals the importance of the anthraquinone moiety in exerting the inhibitory activity of the compound. Our findings recommend that further optimization of this series would benefit colon cancer treatment.

Here, we describe the anticancer activity of our novel bis-triazoles MS47 and MS49, developed previously as G-quadruplex stabilizers, focusing specifically upon the human melanoma MDA-MB-435 cell line. At the National Cancer Institute (NCI), USA, bis-triazole MS47 (NCS 778438) was evaluated against a panel of sixty human cancer cell lines, and showed selective, distinct multi-log differential patterns of activity, with GI₅₀ and LC₅₀ values in the sub-micromolar range against human cancer cells. MS47 showed highly selective cytotoxicity towards human melanoma, ovarian, CNS and colon cancer cell lines; in contrast, the leukemia cell lines interestingly showed resistance to MS47 cytotoxic activity. Further studies revealed the potent cell growth inhibiting properties of MS47 and MS49 against the human melanoma MDA-MB-435 cell line, as verified by MTT assays; both ligands were more potent against cancer cells than MRC-5 fetal lung fibroblasts (SI > 9). Melanoma colony formation was significantly suppressed by MS47 and MS49, and time- and dose-dependent apoptosis induction was also observed. Furthermore, MS47 significantly arrested melanoma cells at the G0/G1 cell cycle phase. While the expression levels of Hsp90 protein in melanoma cells were significantly decreased by MS49, corroborating its binding to the G4-DNA promoter of the Hsp90 gene. Both ligands failed to induce senescence in the human melanoma cells after 72 h of treatment, corroborating their weak stabilization of the telomeric G4-DNA.