br Acknowledgements This work was supported by the

Acknowledgements This work was supported by the Victorian Government Operational Infrastructure Support Program. KAB is supported by the Mavis Robertson Fellowship from the National Breast Cancer Foundation (NBCF; ECF-16-004), by an NBCF Novel Concept Award (NC-14-011), and by NHMRC project grant (GNT1061800). CG was supported by a BeIPD-Marie Curie COFUND fellowship from the University of Liège, Belgium.
Introduction Breast cancer is one of the most common cancer types. Surgical methods, radiotherapy, and reversible inhibition of Demethoxycurcumin synthesis or its interaction with drugs constitute the basis of treatment for breast cancer. The investigated history of breast cancer suggests that many tumors occur and develop through estrogen-dependent mechanisms. Accordingly, it can be assumed that estrogen deprivation may prevent the formation of these cancers or may result in the regression of occurred tumors.3, 4 The target of this suppression is the inhibition of the aromatase enzyme responsible for the cyclization and structuring of estrogen. These processes are mechanically constructed by inhibiting the last step, in which the aromatic ring in the steroid structure is formed during biosynthesis. In this step, the ketone group at position 3 is converted to 3-hydroxyl by dihydronicotinamide-adenine dinucleotide phosphate (NADPH). The methyl group at position 19 is eliminated and aromatization of the A-ring of estrogen takes place. These processes are responsible for aromatase, a cytochrome P450 derivative, and related flavoproteins.6, 7 The key role of aromatase in estrogen biosynthesis makes this enzyme a promising candidate for the development of drugs to be used in the treatment of endocrine-derived tumors.8, 9 Due to the serious side effects of steroid-derived inhibitors involved in the treatment regimen, research in recent years has mostly focused on the development of non-steroidal derivatives and undertaking clinical trials.10, 11 Non-steroidal compounds usually contain triazole structures attached to the aromatic ring. In addition, it forms part of the ring structure in functions that are coordinated with the iron in the haem group of the aromatase enzyme and effectively inhibit hydroxylation reactions for aromatization. Linked to the heme group and the active site, this combination is responsible for a high effect and target specificity. By changing the triazole system with bioisosteres and improving the aromatic/cyclic structures in the side chain selectively inhibits the aromatase enzyme.14, 15 Studies on pyrimidinyl thiazole derivatives have shown varying pharmacological properties through anti-inflammatory, histamine H2 receptor antagonistic, and antibacterial activities on Helicobacter pylori.16, 17 In a study investigating the aromatase activity of the thiazole ring system, nitrogen containing heterocyclic structures were attached using diarylmethane and diarylmethanol intermediate chain structures, and the compounds showed enzyme inhibition at the nanomolar level in in vitro experiments. In another study, 2-bromo or non-substituted thiazole structures linked to the free nitrogen group of the 4-amino-1,2,4-triazole structures by the methyl bridge at position 5 were found to have an inhibitory activity on the aromatase enzyme. A similar situation was observed in the work of Shibata et al., in which the activity of aromatase enzyme was obtained by adding diazole, triazole and 4-cyanophenyl structures to a carbon bridge as well as thiazole and benzothiazole rings. In 2008, Eriksson et al. found that combining different thiazole derivatives/analogs with tamoxifen showed a high aromatase inhibitor activity and a regression in the proliferation of breast cancer cells at the micromolar level. Thiazole and phenol groups in resveratrol, thiazofurin, and bleomycin are common functionals exhibiting anticancer activity in the structure of natural compounds and drug molecules. The resveratrol structure is able to modulate many steps in carcinogenesis; however, despite its high efficiency, this structure also has certain disadvantages. In the literature, it has been found that the effect of aromatase inhibition increases at a high rate when the ethylenic structure of resveratrol is replaced with thiadiazole, and phenolic groups are replaced with pyridines.22, 23 Furthermore, replacing the central ring system of the resveratrol analogues by 1,3-thiazole ring (IV) results in an aromatase inhibitor activity of 6000 times greater than the original structure (I). In particular when it is nitrogen heterocyclic ring (III,IV), the aromatic side chains at 2nd and 4th positions of central ring systems seems to be significantly responsible for the enhanced activity (Fig. 1).