Non-steroidal aromatase inhibitor

Oral administration of Anastrozole to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/m 2 basis and 9 times higher than the AUC 0-24 hr found in postmenopausal volunteers at the recommended dose). Pre-implantation loss of ova or fetus was increased at doses equal to or greater than mg/kg/day (about one-fifth the recommended human dose on a mg/m 2 basis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans.

The synthesis and in vitro biological evaluation (JEG-3 cells) of a series of novel and potent aromatase inhibitors, prepared by microwave-enhanced Suzuki cross-coupling methodology, are reported. These compounds possess a biphenyl template incorporated with the haem-ligating triazolylmethyl moiety, either on its own or in combination with other substituent(s) at various positions on the phenyl rings. The most potent aromatase inhibitor reported herein has an IC 50 value of  n M , although seven of its congeners are also highly potent (IC 50 ≤ n M ). They all bear the (5-triazolylmethyl-2-cyano)biphenyl structural motif. Docking of representative compounds into a homology model of human aromatase assists in the rationalisation of the SAR derived from the in vitro biological results and supports a crucial role for a cyano group on the “A” phenyl ring, which is accessible to hydrogen bond interactions with Ser 478. Further development of these compounds as potential therapeutic agents for the treatment of hormone-dependent breast cancer is warranted given the high level of potency observed for this class of aromatase inhibitor in vitro.

BRCA2 gene is located on chromosome 13q12 and also classified as a tumour suppressor gene; though shares no homology with the BRCA1 gene. However, it can bind with BRCA1 to participate in DNA damage response pathway. BRCA2 protein functions as a mediator of the core mechanism of homologous recombination. Its mutations are linked to breast carcinomas that are ER and PR positive.  Though rarely associated with basal-like phenotype but still linked to a higher grade (II or III) when compared to age-matched sporadic cases

Drugs like exemestane and other steroidal aromatase inhibitors have a steroidal structure that competes with the natural aromatase substrate androstenedione . [11] The inhibitor must share important structural features with the endogenous substrate, and as features of the androgens , allowing them to interact with the catalytic site on the enzyme protein. This renders the steroidal aromatase inhibitors inherently selective. [13] Due to its selective inhibition it will not affect the production of the other steroids in the estrogen biosynthetic pathway. [9]

Research suggests the common table mushroom has anti- aromatase [17] properties and therefore possible anti-estrogen activity. In 2009, a case-control study of the eating habits of 2,018 women in southeast China revealed that women who consumed greater than 10 grams of fresh mushrooms or greater than 4 grams of dried mushrooms per day had an approximately 50% lower incidence of breast cancer. Chinese women who consumed mushrooms and green tea had a 90% lower incidence of breast cancer. [18] However the study was relatively small (2,018 patients participating) and limited to Chinese women of southeast China.

Non-steroidal aromatase inhibitor

non-steroidal aromatase inhibitor

Drugs like exemestane and other steroidal aromatase inhibitors have a steroidal structure that competes with the natural aromatase substrate androstenedione . [11] The inhibitor must share important structural features with the endogenous substrate, and as features of the androgens , allowing them to interact with the catalytic site on the enzyme protein. This renders the steroidal aromatase inhibitors inherently selective. [13] Due to its selective inhibition it will not affect the production of the other steroids in the estrogen biosynthetic pathway. [9]

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