Design, synthesis, and biological evaluation of new raloxifene analogues of improved antagonist activity and endometrial safety.

Raloxifene agonism of estrogen receptor (ER) in post-menopausal endometrium is not negligible. Based on a rational drug design workflow, we synthesized 14 analogues of raloxifene bearing a polar group in the aromatic ring of the basic side chain (BSC) and/or changes in the bulkiness of the BSC amino group. Analogues with a polar BSC aromatic ring and amino group substituents of increasing volume displayed increasing ER antagonism in Ishikawa cells. Analogues with cyclohexylaminoethoxy (13a) or adamantylaminoethoxy BSC (13b) lacking a polar aromatic ring displayed high ER-binding affinity and ER antagonism in Ishikawa cells higher than raloxifene and similar to fulvestrant (ICI182,780). The endometrial surface epithelium of immature female CD1 mice injected with 13b was comparable to that of vehicle-treated mice, while that of mice treated with estradiol, raloxifene or 13b in combination with estradiol was hyperplastic. These findings indicate that raloxifene analogues with a bulky BSC amino group could provide for higher endometrial safety treatment of the menopausal syndrome.

The microbiology and treatment of human mastitis.

Mastitis, which is generally described as an inflammation of breast tissue, is a common and debilitating disease which frequently results in the cessation of exclusive breastfeeding and affects up to 33% of lactating women. The condition is a primary cause of decreased milk production and results in organoleptic and nutritional alterations in milk quality. Recent studies employing culture-independent techniques, including metagenomic sequencing, have revealed a loss of bacterial diversity in the microbiome of mastitic milk samples compared to healthy milk samples. In those infected, the pathogens Staphylococcus aureus, Staphylococcus epidermidis and members of corynebacteria have been identified as the predominant etiological agents in acute, subacute and granulomatous mastitis, respectively. The increased incidence of antibiotic resistance in the causative species is also a key cause of concern for treatment of the disease, thus leading to the need to develop novel therapies. In this respect, probiotics and bacteriocins have revealed potential as alternative treatments.