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Background: Breast cancer is the second leading cause of mortality among women worldwide. Anticancer agents consisting
of hybrid molecules are used to improve efficacy and reduce drug resistance. Alteration of different genes is involved in the
development of cancer. Consequently, novel anticancer drugs with increased selectivity and specificity are required to overcome
limitation of current drugs. A variety of synthetic steroid derivatives have been contrived, most these derivatives can interact
with the steroid receptors because of a similarity of shape. Also, the investigation of modified steroid derivatives condensed
with various heterocyclic rings has a great attention. Impaired apoptosis and metastasis are critical in cancer development and
is a major barrier to effective treatment.
Methods: Several progesterone derivatives were synthesized. The structure of the newly derivatives was elucidated and
confirmed using the analytical and spectral data. The newly synthesized progesterone derivatives, compounds 1, 2, 3, 4, 5, 6 and
7 were tested for their cytotoxic effects against human breast cancer cells (MCF-7) using neutral red uptake assay. Using QRTPCR
(Quantitative Real Time-Polymerase Chain Reaction), the expression levels of P53, P21, Cdc2, Bcl-2, Survivin, CCND1,
VEGF, HIF-1�±, FGF-1, MMP-2, MMP-9, Ang-1 and Ang-2 genes were investigated.
Results: All tested compounds showed low IC50 values that were comparable to that of tamoxifen. The most active compounds
against MCF-7 cancer cell line was in the descending order of 5>1>2>6>4>7>3. The study revealed that all newly synthesized
compounds down-regulated the expression levels of BCL-2, surviving, VEGF, Ang-2 and MMp-9. Compound 2-7 downregulated
CCND1 gene expression, nevertheless, this was only significant in case of compounds 2, 3 and 6. However, P53
were up-regulated by compounds 3. Moreover, compound 1 significantly down-regulated MMP-2 and compound 3 and 7
significantly down-regulated FGF-1.
Conclusion: This study introduced promising pro-apoptotic and anti-metastatic anticancer agents acting through the
regulation of key regulators of apoptosis, cell cycle and metastasis related genes.