Synthesis And Antifertility & Anticancer Activities Study Of Anordiol Derivatives

China is a developing country where have the most population in the world.Large population and relative shortage of resources,weak environmental carrying capacity is China's basic national conditions at this stage.Population issues are the key factors that related to China's economic and social development.And the practice of family planning is one of the important means for controlling the population.Among them, the use of contraceptives is most convenient and extensive.That has played a tremendous role in control of the population.It will help women avoid pregnancy,the better protect women's physical and mental health.Anordrin has first been synthesized and developed in China in 1970's.Originally it was used as anti-early pregnancy contraceptive,then as visiting contraceptive.In fact, anordiol is its active structure in vivo instead of anordrin.The clinical application stheme of anordrin is rather complex,together with poor absorption,rather higher clinical dosage but comparative effectiveness,as well as estrogenic side effect and paralleling a kind of early-pregnancy sickness such as nausea and vomiting.Many medicinal researchers are still interested in studing anordrin drug application, not only its pharmacologic and cIinical effectives,but also its analog synthesis and screening to find good candidate compounds with higher bioactivity and lower side-effects.Comprehensive on anordrin structure's transformation,we found the majority of derivatives that retain the "A-nor-steroidal molecular structure frame" and replace anordrin's side chains and substituted groups have a certain biological activity of anti-fertility,many of whom have the higher activity.China's scientific researchers have found anordrin has anti-tumor effects in 1989 and confirmed that theα-isomer played such a role.Later,they found the anordrin can inhibit variety of tumors,suggesting that the drug can be used as a prevention or differentiation agent and play a role in the anti-tumor adjuvant chemotherapy.Dienogest has been registered in the European market in 2000.This is so far the only one of 17-nonacetylene group of progestogen contraceptive drug.Its progesterone activity is 10 times higher than D-18-methyl ethynodiol.It also has good hormones-endocrine characteristics,bioavailability,low toxicity and no genetic toxicity hazards.In this thesis,referring to dienogest's molecular structure features,we replaced anordiol's 2α,17α-ethynyl to CH₂R while remaining "A-nor-steroidal frame".We tried to introduce lipophilic aromatic ring,sulfide,and other key elements to increase the fat-soluble,or the introduction of the hydrophilic amino so that the water-solube increased.And to compare the biological activity of these two types compounds with anordiol.Throughout the process of synthesis,we changed anordrin's 17αor 2α,17α-ethynyl into 17 or 2,17-ketone firstly.Then,the product reacted with dimethyl sulfonium methylide and became 17-monospiro or 2,17-dispiro.Finally,some nucleophilic reagents that we selected reacted with the two key intermediates bearing mono-or double spirooxiran respectively and got two serial compounds.In the proceeding of synthesis key intermediate 17-monoketone,we mainly reference to the original routh of our laboratory.But after analysis the compounds' molecular conformation and reaction mechanism,we changed the conditions and the yield can be increased from 20%to 45%.In addition,some studies have proved that anordrin's 2-dimensional structure has a decisive impact of the anti-fertility and anti-tumor activity.So it is essential to confirm the dimensional structure of open-loop products.We proved that these we have synthetic compounds as a physiological activity of theα-isomer by NMR. Use a similar method,we synthesize seven analogues of dienogest.Then we screened the 37 compounds with rat luteal cells in vitro bio-test.Results showed that 10 anordiol's analogues have excellenter anti-fertility bioactivity than positive control.And among 7 dienogest's analogues,2 analogues have excellenter anti-fertility bioactivity than positive control.It is reported that anordrin has not only anti-fertility but also anti-tumor activity. Therefor,we conducted a preliminary test on the 30 anordiol analogues' activity of inhibit ovarian cancer cells in vitro.The results showed that the majority have stronger anti-tumor activity than anordiol.Primary anti-fertility and anti-tumor tests show—anordiol analogues that is reconstructed and synthesized by us still possess excellent bioactivity.Its 2, 17-acetylene is not an essential function,which provide a new way of thinking for the future transformation of the structure.We shall go on studying these two serials compounds' chemical structure relationship with their bioactivity.And the compounds selected having best bioactivity shall be screened by anti-fertility and anti-tumor bio-test in vivo.