Natural products have been a rich source of agents of value in medicine. They have also inspired, at various levels, the fashioning of nonnatural agents of pharmaceutical import. Hitherto, these nonnatural derivatives have been primarily synthesized by manipulating the natural product. As a consequence of major innovations in the subscience of synthetic methodology, the capacity of synthesis to deal with molecules of considerable complexity has increased dramatically. In this paper, we show by example some total syntheses which draw from strategy-enabling advances in methodology. Moreover, we show how these capabilities can be used to discover and develop new agents of potential pharmaceutical value without recourse to the natural product itself.

Small molecule natural products in the discovery of therapeutic agents: the synthesis connection.

Oral contraceptive steroids are of 2 types: oestrogens, of which ethinyloestradiol is the most important, and progestagens, of which levonorgestrel and norethisterone are the most commonly used. All these steroids can be measured by a number of analytical techniques but there is little doubt that radioimmunoassay is the most convenient. All the steroids are well absorbed in humans but while levonorgestrel is completely bioavailable, norethisterone has an average bioavailability of 70%. Ethinyloestradiol, too, is subject to presystemic metabolism with a mean bioavailability of 40 to 45%. The main site of presystemic metabolism is the gut wall, with the production of ethinyloestradiol sulphate. The progestagens norethynodrel, ethynodiol diacetate and lynoestrenol are quantitatively metabolised to norethisterone. The pharmacokinetics of the contraceptive steroids are best described by a 2-compartment open model. The terminal plasma half-life of levonorgestrel varies from 11 to 45 hours and of norethisterone from 5 to 14 hours. The β-phase half-life of ethinyloestradiol varies from 6 to 20 hours. The apparent volume of distribution of these contraceptive steroids (after intravenous administration) is between 1.5 and 4.3 L/kg. During long term treatment with oral contraceptive steroids, steady-state plasma concentrations of ethinyloestradiol (24 hours after administration) are between 10 and 200 pg/ml. Plasma concentrations of norethisterone and levonorgestrel at steady-state are higher than predicted from the single-dose kinetics because of enhanced binding of the progestagens following the induction of sex hormone binding globulin (SHBG) by ethinyloestradiol. Concentrations are in the range of 1.6 to 15.2 ng/ml for norethisterone and 0.8 to 4.5 ng/ml for levonorgestrel. All the contraceptive steroids are bound to proteins in plasma. Ethinyloestradiol is 97 to 98% bound to plasma albumin. The progestagens are bound both to albumin (levonorgestrel 93 to 95%; norethisterone 79 to 80%) and more specifically to SHBG. The binding capacity of SHBG can be enhanced by treatment with ethinyloestradiol or with more conventional enzyme-inducing drugs such as phenobarbitone, carbamazepine or rifampicin. Norethisterone and levonorgestrel are chiefly metabolised by reduction in the A ring and this is followed by conjugation with glucuronide or sulphate. The metabolism of levonorgestrel is stereoselective. Ethinyloestradiol is primarily hydroxylated at the 2 position but a wide variety of hydroxylated and methylated metabolites are formed and these are present both free and as glucuronide and sulphate conjugates. Ethinyloestradiol is conjugated directly at the 3 position (unlike the progestagens) and thus is liable to enterohepatic recirculation. Ethinyloestradiol sulphate concentrations in plasma are many times higher than that of the unchanged drug. The oral contraceptive steroids are involved in drug interactions of clinical significance. While the effect of contraceptive steroids on other drugs is small and unlikely to be of clinical significance, failure of contraception often occurs if enzyme-inducing agents such as rifampkin, phenobarbitone or carbamazepine are coadministered. Oral antibiotics do not seem to cause a significant loss of contraception in the large majority of women. Vitamin C will enhance the effect of contraceptive steroids by competing for sulphate conjugation in the gut wall, thus leading to increased bioavailability of ethinyloestradiol.

Clinical pharmacokinetics of oral contraceptive steroids.

Inhibition of ovulation in women by chronic treatment with a stimulatory LRH analogue--a new approach to birth control?

Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids

Optimized reaction conditions using a novel aminocinchona catalyst and TBA as the additive are developed for the asymmetric condensation of aldehydes with dialkylmalonates.

Richard W Rees

Papers

856. Totally synthetic steroid hormones. Part II. 13β-Alkylgona-1,3,5(10)-trienes, 13β-alkygon-4-en-3-ones, and related compounds

The identification of some human metabolites of norgestrel, a new progestational agent.

Anti-ovulatory/anti-pregnancy effects of [D-Phe2]- LRH analogs administered early in the rat estrous cycle

Antimalarial and other biological activities of some 2'-alkyl and 2'-aryl derivatives of cinchona alkaloids.

Synthesis and amebicidal activities of some 1',2'-secoemetine derivatives.