Musiliyu A. Musa

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.

Synthesis and antiproliferative activity of coumarin-estrogen conjugates against breast cancer cell lines

The syntheses and cytotoxic activity of coumarin-estrogen conjugates are described. In vitro results indicated that conjugates 10, 11 and 13 show growth inhibitory activities at 5-dose concentration (100, 10, 1, 0.1, 0.01 muM) against the following NCI-7- human breast cancer cell lines: BT-549, HS 578T, MCF 7, MDA-MB-231/ATCC, MDA-MB-435, NCI/ADR-RES, and thus serve as new leads for further development of antibreast cancer agent.

In vitro Antiproliferative Activity of Benzopyranone Derivatives in Comparison with Standard Chemotherapeutic Drugs

The cytotoxic activities of five new benzopyranone derivatives containing basic amino side chain are described. Their cytotoxicities against ER(+) MCF‐7 and ER(–) MDA‐MB‐231 human breast cancer cell lines, and Ishikawa human endometrial cell line were determined after 72 h drug exposure employing CellTiter‐Glo assay at concentrations ranging from 0.01–1.0 × 105 nM. The antiproliferative activities of these compounds were compared to tamoxifen (TAM), 4‐hydroxytamoxifen (4‐OHT, active metabolite of tamoxifen), and raloxifene (RAL). In‐vitro results indicated that compounds 9, 10, 12, and 13 were more potent than TAM against the human breast cancer cell lines with IC50 < 20 µM. The in‐silico structure–activity relationships of these compounds and their binding mode within the estrogen receptor (ER) binding site using AutoDock vina are discussed.

Synthesis and in vitro evaluation of 3-(4-nitrophenyl)coumarin derivatives in tumor cell lines

Coumarins are naturally-occurring compounds that have attracted considerable interest due to their numerous biological activities depending on their pattern of substitution on the coumarin molecule. In this present investigation, we synthesized 3-(4-nitrophenyl)coumarin derivatives (9a-e) and evaluated their in vitro cytotoxic effect on human lung (A549), breast (MDA-MB-231) and prostate (PC3) cancer cell lines for 48 h using crystal violet dye binding assay. Cytotoxic effects of the most active compound on normal human lung (MRC-9) and breast (MCF-10A) cell lines, cell cycle analysis using flow cytometry and mitochondrial membrane potential (MMP) using Tetramethyl Rhodamine Methyl Ester (TMRM; rhodamine-123) fluorescent dye were also examined. Among the compounds that were evaluated, 9c showed cytotoxic effect (active), caused significant cells arrest (p<0.05) in G0/G1 and S phases of cell cycle and loss of MMP in A459, MDA-MB-231 and PC3 cell lines. Additionally, the cytotoxic effect of 9c was compared to reference drugs (Coumarin and Docetaxel) for comparative study. These results further demonstrate that acetoxy group at C-7 and C-8 positions of 9c are responsible for the observed cytotoxic effect in these cancer cell lines.

Synthesis and Biological Activity of 3-N-Substituted Estrogen Derivatives as Breast Cancer Agents

3-N-substituted-estrogen derivatives were synthesized and characterized. Their antiproliferative activities against human ER (+) MCF-7 (Breast), ER (-) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines were determined after 72 hours drug exposure employing CellTiter-Glo assay at concentrations ranging from (0.01-100,000 nM). The antiproliferative activities of these compounds were compared to tamoxifen (TAM), 4-hydroxytamoxifen (4-OHT, active metabolite of tamoxifen) and raloxifene (RAL). In vitro results indicated that compound 5 (IC50 = 12 µM) displayed comparable antiproliferative activity against MDA-MB 231 cell line; while compounds 6, 7 and 13 (IC50 = 12 µM) displayed higher activity against MCF-7 and Ishikawa cell lines, in comparison to TAM activity (19-33 µM).

7,8-Dihydroxy-3-(4-nitrophenyl)coumarin induces cell death via reactive oxygen species-independent S-phase cell arrest: MUSA et al.

We herein report the synthesis and in vitro cytotoxicity of 3‐arylcoumarin derivatives (6a‐f and 7a‐f) in human liver (HepG2), prostate (LNCap), and pancreatic (BxPC3) cancer cell lines. Among the tested compounds, 7,8‐dihydroxy‐3‐(4‐nitrophenyl) coumarin (7b) showed the highest cytotoxicity in the HepG2 cell line. The mechanism of cytotoxic action indicated that compound (7b) arrested HepG2 cells at the S phase of the cell cycle progression, induced loss of mitochondrial membrane potential, and caused reactive oxygen species (ROS)‐independent cell death. The cell viability result of pretreated HepG2 cells with antioxidant N‐acetylcysteine followed by compound (7b) treatment and the free radical scavenging activities of compound (7b) confirmed the ROS‐independent cell death. These results demonstrate that compound (7b) could serve as a valuable template for the development of novel synthetic compounds as potential anticancer agents for hepatocellular carcinoma treatment.

Abstract C51: In vitro cytotoxicity of 3-arylcoumarin derivatives in human prostate (PC3) cancer cell line

Coumarins are classified as a member of the benzopyrone family of compounds with diverse and interesting biological activities. They have been used as therapeutic agents in the treatment of various diseases. In the present study, we evaluated the in vitro cytotoxic activity of 3-arylcoumarins (1-11) in human prostate (PC3) cancer and (WPE1-NA22) normal cell lines at various concentrations (0, 10, 25, 50, 75 and 100 μM) after 48 h treatment using crystal violet dye binding assay. The most active compounds cytotoxicity was examined by cell cycle analysis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) measurement and Bax protein expression. Our findings indicate Result that 8-(acetyloxy)-3-(4-methanesulfonylphenyl)-2-oxo-2H-chromen-7-ylacetate (11) showed cytotoxic activity in PC3 cancer cell line (LD50 = 35.0 μM) and no cytotoxic activity in WPE1-NA22 normal cell line (inactive; LD50 = >100 μM) in comparison to the other synthesized analogs. Furthermore, It caused significant cells arrest (p Grant Support: Research supported by Florida A & M University Title III Program Citation Format: Musiliyu A. Musa, Moise Y. Joseph, Lekan M. Latinwo, Veera L. Badisa. In vitro cytotoxicity of 3-arylcoumarin derivatives in human prostate (PC3) cancer cell line. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C51. doi:10.1158/1538-7755.DISP13-C51

Synthesis and Evaluation of Estradiol Derivatives as Anti-Breast Cancer Agents

3-N-alkyloxyestradiol derivatives were synthesized, characterized and tested for activity in MCF-7 human breast cancer cells. Among the compounds, the diisopropyl and piperidinyl derivatives were found to be more active than 4-hydroxytamoxifen (HO-Tam), the active metabolite of tamoxifen based upon IC(50) values. The IC(50)s were correlated with structures using molecular modeling.