Novel p-Functionalized Chromen-4-on-3-yl Chalcones Bearing Astonishing Boronic Acid Moiety as MDM2 Inhibitor: Synthesis, Cytotoxic Evaluation and Simulation Studies.

BACKGROUND: Novel 4-[3-(6/7/8-Substituted 4-Oxo-4H-chromen-3-yl)acryloyl]phenylboronic acid derivatives (5a-h) as well as other 6/7/8-substituted-3-(3-oxo-3-(4-substitutedphenyl) prop-1-enyl)-4H-chromen-4-one derivatives (3a-u) have been designed as p53-MDM2 pathway inhibitors and reported to possess significant cytotoxic properties against several cancer cell lines. OBJECTIVES: The current project aims to frame the structure-anticancer activity relationship of chromen-4-on-3-yl chalcones (3a-u/5a-h). In addition, docking studies were performed on these chromeno-chalcones in order to have an insight into their interaction possibilities with MDM2 protein. METHODS: Twenty-nine chromen-4-on-3-yl chalcone derivatives (3a-u/5a-h) were prepared by utilizing silica supported-HClO4 (green route with magnificent yield) and tested against four cancer cell lines (HCT116, MCF-7, THP-1, NCIH322). RESULTS: Among the series 3a-u, compound 3b exhibited the highest anticancer activity (with IC50 values ranging from 8.6 to 28.4 µM) overall against tested cancer cell lines. Interestingly, para- Boronic acid derivative (5b) showed selective inhibition against colon cancer cell line, HCT-116 with an IC50 value of 2.35 µM. Besides the emblematic hydrophobic interactions of MDM2 inhibitors, derivative 5b was found to exhibit extra hydrogen bonding with GLN59 and GLN72 residues of MDM2 in molecular dynamics (MD) simulation. All the compounds were virtually nontoxic against normal fibroblast cells. CONCLUSION: Novel compounds were obtained with good anticancer activity especially 6- Chlorochromen-4-one substituted boronic acid derivative 5b. The molecular docking study proposed good activity as a MDM-2 inhibitor suggesting hydrophobic as well as hydrogen bonding interactions with MDM2.

Protein expression and molecular analysis of c-myc gene in primary breast carcinomas using immunohistochemistry and differential polymerase chain reaction.

Overexpression of c-myc protein and amplification of c-myc were investigated by immunohistochemistry and differential polymerase chain reaction (dPCR) in 440 formalin-fixed primary breast carcinoma tissues, respectively. Overexpression of c-myc was detected in 45% (199/440) and amplification of c-myc was observed in 25% (112/440) of the primary breast carcinomas. Immunolocalization of c-myc oncoprotein was demonstrated in 35% (8/23) of the comedo subtype, 17% (3/18) of the non-comedo subtype, 37% (15/41) of the comedo DCIS and 49% (20/41) of the adjacent invasive ductal carcinomas, 21% (4/19) of the non-comedo DCIS and 37% (7/19) of the adjacent invasive lesions, 49% (133/270) of the invasive ductal carcinomas, 33% (11/33) of the invasive lobular carcinomas, 29% (6/21) of the colloid carcinomas and 47% (7/15) of the medullary carcinomas. C-myc was amplified in 13% (3/23) of the comedo DCIS, 17% (7/41) of the comedo DCIS and 24% (10/41) of the adjacent invasive ductal carcinomas, 30% (82/270) of the invasive ductal carcinomas, 21% (7/33) of the invasive lobular carcinomas, 14% (3/21) of the colloid carcinomas and 24% (4/15) of the medullary carcinomas. Amplification of c-myc was noted in 16% (3/9) of the invasive ductal carcinomas but not in the adjacent non-comedo DCIS lesions. A significant association (P<0.05) was observed between in situ components and adjacent invasive lesions for c-myc expression and amplification. Overexpression of c-myc protein was significantly correlated with poorly differentiated (P<0.05) and high proliferation index (Ki-67) (P<0.05) tumors but not with lymph node metastases (P>0.05), patient age (P>0.05) and estrogen receptor status (P>0.05). Significant relationship was also noted between amplification of c-myc and absence of estrogen receptor (P<0.05), high histological grade (P<0.05) and high proliferation index (Ki-67) (P<0.05). No relationship was seen with nodal status (P>0.05) and patient age (P>0.05). Majority of the Malaysian female patients are from younger age group (<50 years old) but overexpression and amplification of c-myc was not statistically associated with patient age (P>0.05) indicating that these alterations may be independent events of patient age. The above observations suggest that overexpression and amplification of c-myc could play an important role in tumor progression from non-invasive to invasive and, also, it may have the potential as a marker of poor prognosis of breast cancer.