Design, synthesis and in vitro anticancer activity of some new lomefloxacin derivatives.

Our main goal was to design and synthesize novel lomefloxacin derivatives that inhibit the topoisomerase II enzyme, leading to potent anticancer activity. Lomefloxacin derivatives substituted at position 3 and 7 were synthesized and screened for cytotoxic activity utilizing 60 different human cancer cell lines. Furthermore, compounds 3a,b,c,e that revealed potent broad-spectrum anticancer activity (with mean percent GI more than 47%) were further evaluated using five dose concentrations and calculating the GI50. Compound 3e was then evaluated for cell cycle analysis and demonstrated cell cycle arrest at the G2-M phase. Moreover, the mechanism of action was determined by determining the topoisomerase inhibitory activity and the molecular modeling study. Compounds 3a,b,c,e showed broad spectrum anticancer activity. Lomefloxacin derivative 5f showed selective cytotoxic activity against melanoma SK-MEL-5 cell line. Compound 3e demonstrated comparable topoisomerase II inhibition to doxorubicin with IC50 of 0.98 µM.

Design, synthesis, and biological evaluation of new celecoxib analogs as apoptosis inducers and cyclooxygenase-2 inhibitors.

Series of new celecoxib analogs were synthesized to assess their anticancer activity against the MCF-7 cell line. Four compounds, 3a, 3c, 5b, and 5c, showed 1.4-9.2-fold more potent anticancer activity than celecoxib. The antiproliferative activity of the most potent compounds, 3c, 5b, and 5c, seems to be associated well with their ability to induce apoptosis in MCF-7 cells (18-24-fold). This evidence was supported by an increase in the expression of the tumor suppressor gene p53 (4-6-fold), the elevation in the Bax/BCL-2 ratio, and a significant increase in the level of active caspase-7 (4-7-fold). Moreover, compounds 3c and 5c showed significant cyclooxygenase-2 (COX-2) inhibitory activity. They were also docked into the crystal structure of the COX-2 enzyme (PDB ID: 3LN1) to understand their mode of binding.

Recent advances in the development of celecoxib analogs as anticancer agents: A review.

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) designed to be a selective cyclooxygenase-2 (COX-2) inhibitor. It was approved by the U.S. Food and Drug Administration for the treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis. Additionally, celecoxib demonstrated potent antitumor and chemopreventive effects in vitro, in vivo, and in patients. The mechanism of celecoxib's chemopreventive effect is still not fully identified, but it is assumed to be multifactorial. Celecoxib's anticancer activity has been described both as independent of and dependent on its COX-2 inhibitory activity. The current review summarizes the recent advances published between 2000 and 2022 on the structure-based optimization of celecoxib to develop compounds with promising anticancer activity. The structure-activity relationships of celecoxib analogs are discussed, which may be beneficial in the design and development of novel analogs as potent antiproliferative agents in the future.

Design and Synthesis of Novel Celecoxib Analogues with Potential Cytotoxic and Pro-apoptotic Activity against Breast Cancer Cell Line MCF-7.

BACKGROUND: Breast cancer is currently the leading cause of worldwide cancer incidence exceeding lung cancer. In addition, breast cancer accounts for 1 in 4 cancer cases and 1 in 6 cancer deaths among women. Cytotoxic chemotherapy is still the main therapeutic approach for patients with metastatic breast cancer. OBJECTIVE: The aim of the study was to synthesize a series of novel celecoxib analogues to evaluate their anticancer activity against the MCF-7 cell line. METHODS: Our design of target compounds was based on preserving the pyrazole moiety of celecoxib attached to two phenyl rings, one of them having a polar hydrogen bonding group (sulfonamide or methoxy group). The methyl group of the second phenyl ring was replaced with chlorine or bromine atom. Finally, the trifluoromethyl group was replaced with arylidene hydrazine-1-carbonyl moiety, which is substituted either with fluoro or methoxy group, offering various electronic and lipophilic environments. These modifications were carried out to investigate their effects on the antiproliferative activity of the newly synthesized celecoxib analogues and to provide a valuable structure- activity relationship. RESULTS: Four compounds, namely 4e-h, exhibited significant antitumor activity. Compounds 4e, 4f and 4h showed 1.2-2 folds more potent anticancer activity than celecoxib. Celecoxib analogue 4f showed the most potent anti-proliferative activity. Its anti-proliferative activity seems to associate well with its ability to inhibit BCL-2. Moreover, activation of the damage response pathway of the DNA leads to cell cycle arrest at the G2/M phase and accumulation of cells in the pre-G1 phase, indicating that cell death proceeds through an apoptotic mechanism. Compound 4f exhibited a potent pro-apoptotic effect via induction of the intrinsic mitochondrial pathway of apoptosis. This mechanistic pathway was proved by a significant increase in the expression of the tumor suppressor gene p53, elevation in Bax/BCL-2 ratio, and a significant increase in the level of active caspase-7. Furthermore, compound 4f showed moderate COX-2 inhibitory activity. CONCLUSION: Celecoxib analogue 4f is a promising multi-targeted lead for the design and synthesis of potent anticancer agents.

Pyrrolo and pyrrolopyrimidine sulfonamides act as cytotoxic agents in hypoxia via inhibition of transmembrane carbonic anhydrases.

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.

Novel nalidixic acid derivatives targeting topoisomerase II enzyme; Design, synthesis, anticancer activity and effect on cell cycle profile.

AIM: Design and synthesis of novel nalidixic acid derivatives of potent anticancer and topoisomerase II inhibitory activities were our major aim. MATERIALS & METHODS: All the newly synthesized nalidixic acid derivatives were submitted to the National Cancer Institute (NCI), Bethesda, USA and were accepted for single dose screening. Further investigation via IC50 determination of the most potent compound 6a against K-562 and SR leukemia cell lines. Finally, the topoisomerase II inhibitory activity, the cell cycle analysis and molecular docking of 6a were performed in order to identify the possible mechanism of the anticancer activity. RESULTS: Compound 6a showed interesting selectivity against leukemia especially K-562 and SR subpanels with IC50 35.29 µM and 13.85 µM respectively. Moreover, compound 6a revealed potent topoisomerase IIα and topoisomerase IIß inhibitory activity compared with known topoisomerase inhibitors such as doxorubicin and topotecan with IC50 1.30 µM and 0.017 µM respectively. Cell cycle analysis indicated that compound 6a induced cell cycle arrest at G2-M phase leading to inhibition of cell proliferation and apoptosis. Molecular modeling demonstrated that the potent topoisomerase inhibitory activity of 6a was due to the interaction with the topoisomerase II enzyme through coordinate bonding with the magnesium ion Mg2+, hydrogen bonding with Asp 545 and arene cation interaction with His 759.

Synthesis, Characterization and Cytotoxicity of Substituted [1]Benzothieno[3,2-e][1,2,4]triazolo [4,3-a]pyrimidines.

A new series of 4-benzyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidines was synthesized motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines and triazolothienopyrimidines. The in vitro cytotoxic activity of some selected compounds was evaluated against two human cell lines: prostate cancer (PC-3) and colon cancer (HCT-116). A preliminary study of the structure-activity relationship of the target compounds was discussed. Most of the synthesized compounds showed remarkable activity on the tested cell lines, while compound 16c had the highest potency against the PC-3 cell line with an IC50 of 5.48 µM compared to Doxorubicin (IC50 = 7.7 µM), the reference standard used in this study. On the other hand, 6c and 18c were the most active against HCT-116 (IC50 = 6.12 and 6.56 µM, respectively) relative to IC50 = 15.82 µM of the standard. Thus, some of the synthesized thienopyrimidine derivatives, specially 6c, 16c and 18c, have the potential to be developed into potent anticancer agents.

Synthesis of some chalcones and pyrazolines carrying morpholinophenyl moiety as potential anti-inflammatory agents.

Chalcones of 2a-f and their corresponding products, pyrazolines 3a-f, were synthesized and evaluated for their anti-inflammatory activity against carrageenan edema in albino rats at a dose of 10 mg/kg. All the compounds of this series showed promising anti-inflammatory activity. The most active compounds of this series, 2a, 2b, and 2d, were found to be most potent. They showed higher percentage of inhibition of edema than the standard drug indomethacin.

Synthesis and antitumor activity of novel 6-aryl and 6-alkylpyrazolo[3,4-d]pyrimidin-4-one derivatives.

A series of new 6-arylpyrazolo[3,4-d]pyrimidin-4-ones and 6-alkylpyrazolo[3,4-d]pyrimidin-4-ones were synthesized. Some of the newly synthesized compounds were tested in vitro on human colon tumor cell line (HCT116). Most of the test compounds exploited potent antitumor activity, especially compound 10a which displayed the highest activity among the test compounds with IC(50) equal to 0.47 µg/mL.

Synthesis and anti-inflammatory activity of certain piperazinylthienylpyridazine derivatives.

In this study, a novel series of 2-(4-substituted piperazin-l-ylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones (3a-f), 2-(4-substituted piperazin-l-yl carbonylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones (4a-c) and 2-[2-(4-substituted piperazin-l-ylcarbonylethyl)]-6-(thien-2-yl)-2H-pyridazin-3-ones (5a,b) were prepared from 6-(thien-2-yl)-2H- pyridazin-3-one (1). In addition, 3-(4-substituted piperazin-l-ylcarbonyl methyl thio)-6-(thien-2-yl) pyridazines (6a-c) and 3-[2-(4-substitutedpiperazin-1-ylcarbonyl ethylthio]-6-(thien-2-yl) pyridazines (7a,b) were synthesized. Furthermore, 5-(4-substituted piperazin-l-ylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones (12a,b) were prepared. The structures of the new compounds were confirmed by elemental analysis as well as by 1H-NMR, IR and MS data. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity against carrageenan-induced paw edema at a dose of 10 mg/kg using indomethacin as the reference standard.

Synthesis and antimicrobial activity of certain novel quinoxalines.

In this study, certain 3-methyl-2-[4-(substituted amino carbonyl)anilino] quinoxalines, (2a-d) and (3a-d), were synthesized from the new key compound 2-[4-(ethoxycarbonyl)anilino]-3-methyl quinoxaline (1). In addition, a series of 2-[4-(arylidene hydrazinocarbonyl)anilino]-3-methyl quinoxalines (5a-e), as well as their cyclized oxadiazolinyl derivatives (6a-e), and a series of 2-[4-N2-acylhydrazinocarbonyl) anilino]-3-methyl quinoxalines (7a-d), as well as their cyclized oxadiazoiyl derivatives (8a-d) were also prepared. Some of these derivatives were evaluated for antimicrobial activity in vitro. It was found that all the selected compounds exhibit antimicrobial activity and that compound 5b had a broad spectrum of activity.