Cytotoxicity and gene expression profiles of novel synthesized steroid derivatives as chemotherapeutic anti-breast cancer agents

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 22; pp. 6860 - 6872
• Main Authors: Elmegeed, Gamal A., Khalil, Wagdy K.B., Mohareb, Rafat M., Ahmed, Hanaa H., Abd-Elhalim, Mervat M., Elsayed, Ghada H.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.11.2011; Elsevier
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Aromatase - biosynthesis; Aromatase - genetics; Biological and medical sciences; Breast cancer; breast neoplasms; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Line, Tumor; chemistry; chemotherapy; Cytotoxicity; doxorubicin; Drug Screening Assays, Antitumor; Female; Gene expression; Gene Expression - drug effects; Gene Expression Profiling; General aspects; genes; Heterocycles; Humans; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; spectral analysis; Steroids; Steroids - chemical synthesis; Steroids - pharmacology; Structure-Activity Relationship; Transcription Factor AP-2 - biosynthesis; Transcription Factor AP-2 - genetics; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; vascular endothelial growth factors; Heterocycles; RT; SRB; DMSO; hAP-2γ; aFGF; Cytotoxicity; TLC; E2; FBS; TGF-α; TGF-β; CYP19; DMF; CBMN; ERβ; ERα; VEGF; JCBN; Breast cancer; Dox; RT–PCR; Gene expression; ER; bFGF; TCA; TNF-α; HER-2/neu; Steroids; Antineoplastic agent; Steroid; Nitrile; Copper Complexes; Structure activity relation; Mammary gland; Chemical synthesis; Reverse transcription polymerase chain reaction; Tumor cell; Human; Sulfonamide; Transition metal Complexes; Malignant tumor; In vitro; Androstane derivatives; Spiran; Gene amplification; Cell line; Pyrimidine derivatives; Cancer
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.09.033

The present study aimed to synthesize and evaluate new potential chemotherapeutic anti-breast cancer agents. Thiazolo-androstane 17 (IC50=2.5μM) exhibited more inhibitory influence on MCF-7 growth than doxorubicin (IC50=4.5μM) after 48h incubation. All the tested steroid derivatives exhibited significant depletion in gene expression of breast cancer related genes. Noteworthy, compounds 17, 20 and 22c showed the most pronounced effect in this respect. Anti-cancer agents which combine two biologically active compounds in one such as steroidal heterocyclic derivatives attain both hormone and cytotoxic effects on cancer cells. The aim of the present study is to synthesize and evaluate new potential chemotherapeutic anti-breast cancer agents. Several pyridazino-, pyrimido-, quinazolo-, oxirano- and thiazolo-steroid derivatives were synthesized. The structure of the novel steroid derivatives was confirmed using the analytical and spectral data. The most structurally promising of the novel synthesized steroid derivatives, compounds 8, 12, 17, 20, 22c, 24c, 30a and 30b, were investigated individually as anti-breast cancer agents against human breast cancer cells (MCF-7) using sulforhodamine B (SRB) assay. The tested compounds 17, 20, 22c and 8 showed potent broad spectrum cytotoxic activity in vitro after 48h incubation. Compound 17 (IC50=2.5μM) exhibited more inhibitory influence on MCF-7 growth than the reference drug doxorubicin (Dox) (IC50=4.5μM) after 48h incubation. Also, the present study showed that all the tested steroid derivatives exhibited significant depletion with various intensities in gene expression of breast cancer related genes (VEGF, CYP19 and hAP-2γ). Noteworthy, compounds 17, 20 and 22c showed the most pronounced effect in this respect.