Khairia M. Youssef

PAC, a novel curcumin analogue, has anti-breast cancer properties with higher efficiency on ER-negative cells

We have investigated here the anti-breast cancer properties of two novel curcumin analogues, EAC and PAC. Apoptosis was assessed by the annexin V/propidium iodide (PI) assay on different breast cancer and normal cells. Immunoblotting analysis determined the effects of these agents on different apoptotic and oncogenic proteins. Furthermore, flow cytometry and Elispot were utilised to investigate the effects on the cell cycle and the production of cytokines, respectively. Breast cancer tumour xenografts were developed in nude mice. Finally, 18F-radiolabeled PAC and curcumin were produced to study their bioavailability and tissue biodistribution in mice. PAC is five times more efficient than curcumin and EAC in inducing apoptosis, mainly via the internal mitochondrial route. This effect was 10-fold higher against ER-negative as compared to ER-positive cells, and ectopic expression of ERα rendered ER-negative breast cancer cells more resistant to PAC. In addition, PAC delayed the cell cycle at G2/M phase with a stronger effect on ER-negative cells. Moreover, PAC exhibited strong capacity as an immuno-inducer through reducing the secretion of the two major Th2 cytokines IL-4 and IL-10. Importantly, PAC significantly reduced tumour size, and triggered apoptosis in vivo. Furthermore, PAC inhibited survivin, NF-kB and its downstream effectors cyclin D1 and Bcl-2, and strongly up-regulated p21WAF1 both in vitro and in tumours. Besides, PAC exhibited higher stability in blood and greater biodistribution and bioavailability than curcumin in mice. These results indicate that PAC could constitute a powerful, yet not toxic, new chemotherapeutic agent against ER-negative breast tumours.

Synthesis of curcumin and ethylcurcumin bioconjugates as potential antitumor agents

Some new curcumin and ethylcurcumin bioconjugates with various functionalities supported on the curcumin skeleton were synthesized and evaluated for antitumor activity. Most of the newly synthesized compounds are more active than curcumin and ethyl curcumin but are less cytotoxic than the reference compound doxorubicin. Surprisingly, many of these compounds are not cytotoxic to noncancer cells. Compounds 5c, 5e, 5g, 5j, 6b, and 6g having 5-methylthiadiazole, 6-methoxy-benzothiazole, diethylaminoethyl and the usual alkylating bis(2-chloroethyl)amino moieties showed the highest cytotoxic activity against SK-MEL cancer cells. Compounds 5k, 6c, and 6g are less cytotoxic to KB cancer cells. Moreover, compounds 5c, 5e, 5j, 5k, 6d, 6e, 6f, and 6g showed cytotoxicity against BT-549 cancer cells with 5j being the most active compound. Curcumin and the new intermediate di-O-chloroacetylcurcumin (3a) were also cytotoxic against the same cell line but are less active than the target compounds. Compound 6b is the only one exhibiting cytotoxicity against SK-OV-3 cancer cells.

Newly Designed and Synthesized Curcumin Analogs with in vitro Cytotoxicity and Tubulin Polymerization Activity

Novel curcumin analogs with 4‐piperidone ring were designed, synthesized, and evaluated for their cytotoxic activities against five different cancer cell lines. 3,5‐bis(4‐Hydroxy‐3‐methoxybenzylidene)‐4‐oxo‐N‐phenylpiperidine‐1‐carbothioamide (XIIe) exhibited considerable cytotoxic activity with IC50 values in 1–2.5 μm range. In silico and in vitro, studies were also performed to predict the binding affinity of the target compounds to the β‐chain of tubulin receptor (PDB code 1SA1) and their abilities to affect microtubules polymerization cycle. 3,5‐bis(3‐Iodo‐5‐methoxy‐4‐propoxybenzylidene)‐N‐acetylpiperidin‐4‐one (VIIa) was found to exert 93.3% inhibition of tubulin and destabilization of microtubules in vitro compared to vincristine while, 3,5‐bis(3,4,5‐trimethoxybenzylidene)‐N‐benzoylpiperidin‐4‐one (XIIc) showed high potency in a different way where it exerted 94.8% stabilization of microtubules in vitro compared to positive control paclitaxel.

Design, synthesis and molecular modeling study of certain VEGFR-2 inhibitors based on thienopyrimidne scaffold as cancer targeting agents

Different series of novel thieno [2,3-d]pyrimidine derivative (9a-d,10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d, 15d and 15 g are among the most active inhibitors with IC50 values of 2.5, 5.48 and 2.27 µM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors.

Medicinal Attributes of Thienopyrimidine Based Scaffold Targeting Tyrosine Kinases and Their Potential Anticancer Activities

Thienopyrimidines (TP), comprising a thiophene ring fused with pyrimidine, are famous bioisosteres to purines, an essential part of the human metabolome. This scaffold has become an interesting structural element in the development of pharmaceutical compounds, due to their wide spectrum applications as cytotoxic agents against different types of human cancer cell lines, cGMP phosphodiesterase inhibitors, and anti‐viral, anti‐inflammatory, and anti‐microbial agents. The structural similarity of this scaffold with adenine made it an excellent moiety to be used in the design of kinase inhibitors. This review focuses on the chemistry of thienopyrimidine derivatives, their potential activities against various kinases, and their structure–activity relationship studies.