The biosynthetic process of steroid hormones

  • Steroid drugs mainly include corticosteroids, sex hormones, progesterone and other types. They are endogenous substances found in the study of the endocrine system of mammals. They are used in maintaining life, mediating sexual function, body development, immune mediation, skin disease treatment and It has a clear role in birth control.


    Steroid drugs have a long history of development, and it has a history of nearly a hundred years. In the 1930s, researchers obtained pure crystals of estrone, estradiol, testosterone, and corticosterone from the glands and analyzed their chemical structure in detail, which was regarded as the beginning of the steroid drug industry. People initially prepared steroidal drugs from cholic acid extracted from the internal organs of animals. Since the discovery of diosgenin in Mexico in the 1950s, except for some special hormone products such as estrogen that need to be extracted from animal urine, almost all steroid drugs have been converted to diosgenin as the starting material for production , Diosgenin and the synthetic technology derived from it have become the main technology in this industry. The synthetic route of the technology is: turmeric → initial materials such as saponin → starting materials such as diene → various steroid hormone intermediates → steroid drugs.


    Ovarian tissue can convert acetate containing 2 carbon atoms into cholesterol, and it can also directly take up cholesterol in the blood circulation as the basic structure of synthetic hormones. Pregnenolone synthesized from cholesterol is considered to be the precursor of all steroid hormones. Pregnenolone is converted into androstenedione 25 ~ estrogen is mainly estradiol and estrone. Estriol is its degradation product. The biological activity of estrogen is estradiol the strongest, followed by estrone, and estriol is the weakest.


    There is a close relationship between estrogen, androgens and progesterone. Progesterone is the precursor of androstenedione and testosterone, and androstenedione and testosterone are the precursors of estrone and estradiol. Although the three basic structures are very similar, But the effect is different.


    It is now understood that the granular cells in the growing follicles and mature follicles before ovulation can also produce progesterone, but the granular cells lack iTa-hydroxylase to stop the synthesis of progesterone. Due to the lack of blood vessels in the granular cell layer, the production of progesterone cannot directly enter the blood circulation, while the inner follicle cells adjacent to the granular cells contain these enzymes. When the synthesized progesterone passes through the inner membrane of the follicle, after the action of 17 shovel hydroxylase in the inner membrane cells of the follicle, the synthesis process continues, and finally estradiol is formed. After ovulation, the blood vessels in the inner membrane of the follicle enter the human corpus corpus, and progesterone can directly enter the blood circulation; at the same time. Follicle inner membrane cells are transformed into follicular membrane corpus luteum cells and become a component of the corpus luteum, therefore. The corpus luteum can also secrete estrogen. Although the granulosa cells before ovulation lack 17a hydroxylase, they are very rich in aromatase, which can convert androstenedione produced by the inner membrane cells of the peripheral follicle into estrone. Then it is converted into estradiol. Therefore, it is believed that estrogen is co-produced by follicular inner membrane cells and granulosa cells.


    Starting from the known ketene compounds, CBS reduction and Ireland-Claisen rearrangement reactions have realized the preparation of chiral acyl radical precursors, and the generated C1 chiral stereochemistry is transferred to the C5 position; acyl radical conjugate addition The formation reaction and intramolecular Heck reaction construct the four-ring skeleton structure of the natural product core, and transfer the C5 chiral stereochemistry to the C10 position to obtain the C10 quaternary carbon chiral center with the correct configuration; the sulfinolactone substrate The controlled dichlorination reaction of olefins introduces challenging C1 and C2 quasi-equal bond dichlorine atoms, the dehydrogenation reaction eliminates the C5 chiral center, and the first total synthesis of clionastatins A and B is completed in 16-17 steps.


    Throughout the synthesis process, the researchers used the strategy of traceless stereochemical relay, that is, the CBS reduction reaction, Ireland-Claisen rearrangement reaction and intramolecular Heck reaction achieve the precision of the C10 quaternary carbon chiral center. Construct. This study demonstrates the high efficiency of the convergent synthesis strategy in the synthesis of complex natural products, and reflects that the synthesis of natural products is still an important means for the identification or modification of complex molecular structures.


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