The mother of the pill.

PIP: The first synthesis of an active ingredient of the pill was performed on October 15, 1951, at Syntex in Mexico City. These preliminary results, obtained in late 1951, encouraged the submission of a synthetic progestin, norethindrone (19-nor-17alpha-ethynyltestosterone), to a number of outside investigators for more extensive biological scrutiny. Norethynodrel, together with many other steroids synthesized in the Searle laboratories, as well as Syntex's norethindrone, were examined by Pincus and collaborators for ovulation inhibition in animals and humans. Contrary to predictions, orally effective steroid ovulation inhibitors became the most widely used method of reversible birth control in most parts of the world some 40 years after their first synthesis. Toward the end of the 1960s, at least 13 international pharmaceutical companies (9 of them US) had active research and development programs dedicated to new advances in the field of contraception. Every drug to which a woman or man is exposed to for long periods of time (e.g., vaccines, systemic contraceptives, cholesterol-lowering agents, antihypertensives) in the end has to pass through large-scale postmarketing experiments. The most damaging was the requirement for 6-year toxicology in beagle dogs, which resulted in enormous development costs. Another setback was a 1986 judgment in Georgia against Ortho Pharmaceutical Company for the amount of $5,151,030 for alleged birth defects caused by the use of its spermicide Ortho-Gynol in spite of overwhelming epidemiological evidence against such a cause-effect relationship. Mifepristone (RU-486) is clearly the most significant new development in birth control as an important alternative to conventional abortion. A priority list of six new contraceptive methods for future development includes a spermicide with antiviral properties, a once-a-month menses inducer, a reliable ovulation predictor, easily reversible male sterilization, a male contraceptive pill, and an antifertility vaccine.^ieng

A new look at male contraception.

As a first step towards a new form of male contraception--sperm cryopreservation, vasectomy and eventual artificial insemination--the military services should begin a large-scale sperm cryopreservation programme.

Biosynthetic studies of marine lipids. 42. Biosynthesis of steroid and triterpenoid metabolites in the sea cucumber Eupentacta fraudatrix.

The saponins, conjugated sterols, and free sterols of the sea cucumber Eupentacta fraudatrix were examined. A total of 85 steroids, twelve of them new, were identified in the free sterol, sulfated sterol, and sterol-xyloside fractions. The free sterol fraction contained 4 alpha,14 alpha-dimethylcholest-9(11)-en-3 beta-ol(6) and 14 alpha-methylcholest-9(11)-en-3 beta-ol(7) together with 18 minor sterols. Examination of the aglycone moieties of the sterol-beta-xyloside fraction afforded 31 different sterols. Cholestan-3 beta-ol (15) and 24-methylcholesta-7,22-dien-3 beta-ol (20) were the major sterols in this group. Cholestanol sulfate (74) and cholesterol sulfate (64) were identified as the major components among the 34 different sterol sulfates present. Finally, cucumariosides G1 (1), C1 (2), C2 (3), H (4), and G2 (5) were isolated from the saponin fraction. Radiolabeling experiments indicated that there are two pathways of sterol biosynthesis in E. fraudratix. The first involves transformation of squalene to produce lanosta-9(11),24-dien-3 beta-ol(parkeol) which is subsequently demethylated to form 4 alpha,14 alpha-dimethylcholest-9(11)-en-3 beta-ol (6) and 14 alpha-methylcholest-9(11)-en-3 beta-ol (7). The second proceeds through squalene to lanosterol which is further metabolized to produce the triterpene saponins, 5 alpha-cholest-7-en-3 beta-ol (19) and its xyloside (49).

Steroid research at Syntex: "the pill" and cortisone.

The period from late 1949 through 1951 was an extraordinarily productive one in steroid chemistry and especially so at Syntex S.A. in Mexico City. Two of the most important Syntex contributions--the synthesis of 19-nor-17 alpha-ethynyltestosterone (norethindrone) and of cortisone from diosgenin--are described from a historical perspective.

PIP: The pharmaceutical industry contributed more to the published record of steroid research during the 1950s than any industry has ever contributed before to any chemical subdiscipline. Syntex, a research-oriented company in Mexico city, contributed much of the publication of industrial research of steroids. Dr. Djerassi arrived at Syntex in 1949 as associate director of chemical research. He conducted partial aromatization studies leading him to the 1st synthesis of an oral contraceptive (OC) on October 15, 1951. This steroid was 19-nor-17 alpha-ethynyltestosterone, later called norethistrone or norethindrone. Syntex submitted the product to a commercial laboratory in Madison, Wisconsin, for biological evaluation. It was indeed the most active, orally effective progestational hormone at the time. Syntex applied for a patent in November 1951. In November 1954, clinical results of norethindrone used to treat various menstrual disorders and fertility problems was presented. G.D. Searle & Co. filed for a patent for the synthesis of the double bond isomer 13 of norethindrone called norethynodrel in August 1953. Acid or human gastric juice converts norethynodrel into norethindrone. Had it not been for Searle using norethindrone in its antimotion sickness drug, Dramamine, Syntex would have filed suit against Searle. Syntex sponsored contraceptive trials with norethindrone. Various incidents prevented Syntex from obtaining US Food and Drug Administration approval to use norethindrone for contraceptive indications before Searle obtained approval to use norethynodrel. By 1964, 3 companies including Syntex were marketing 2 mg doses of Syntex's norethindrone, the most widely used active ingredient in OCs. Dr. Djerassi also played a key role in the synthesis of cortisone from diosgenin, a chemical derived from Mexican yams. This synthesis was a more economical industrial route to cortisone than previous routes.

Minor and trace sterols in marine invertebrates 65. 23-Epidihydrocalysterol: a new cyclopropane-containing sponge sterol.

A new cyclopropane-containing sterol was isolated from the marine sponge Cribrochalina vasculum. The new sterol was characterized by nuclear magnetic resonance and mass spectrometry and the structure was shown to be (23R,24S,28R)-dihydrocalysterol. Implications concerning the biosynthesis of cyclopropane and cyclopropene sterols in sponges are discussed.

Biosynthetic studies of marine lipids 36. The origin of common sterol side chains in eleven sponges using [3-3H]-squalene.

1. [3-3H]-Squalene was fed to 11 marine sponges containing a mixture of "common" sterol side chains. All of these sponges possess significant quantities of cholesterol, but their ability to biosynthesize it differs widely. 2. All the sponges possess significant quantities of delta 22 sterols, yet none of them was able to introduce the delta 22 double bond. 22-Dehydro-24-norcholesterol and 24-methyl-22-dehydro-27-norcholesterol side chains also originate from the diet. 3. These sponges biosynthesized between 40 and 80% of their sterols, a typical value being 70%. The remainder is derived from the diet or by modification of dietary sterols.

Phospholipid studies of marine organisms: 26. Interactions of some marine sterols with 1-stearoyl-2-oleoyl phosphatidylcholine (SOPC) in model membranes.

The thermotropic behavior of multilamellar vesicles (MLV) composed of different mole fractions of various marine sterols and 1-stearoyl-2-oleoyl phosphatidylcholine (SOPC) was examined by differential scanning calorimetry (DSC), and was compared to pure SOPC as well as their mixtures with cholesterol. The marine sterols investigated were capable of interacting with the phospholipid bilayers. Upon addition of marine sterols, the apparent transition temperature (Tm) of SOPC decreased significantly. Desmosterol (cholesta-5,24-dien-3 beta-ol) had the least interaction with SOPC, as reflected by the larger delta H values of its mixtures with the phospholipid. Fucosterol (24-ethylcholesta-5,24(28)-dien-3 beta-ol) showed a non-linear trend as the mole percent of the sterol increased. Mixtures of sutinasterol (24R-24-ethyl-26,26-dimethylcholesta-7,25(27)-dien-3 beta-ol) with SOPC had similar enthalpy values to cholesterol. The shape of the SOPC/marine sterol endotherm and their delta H values were not identical when liposomes prepared by dialysis were compared to MLV.

Metabolism of unusual membrane phospholipids in the marine sponge Microciona prolifera.

Sponges are unique in regard to membrane phospholipid composition. Features virtually without parallel in other organisms are the predominance of the C26-C30 polyenoic acids (demospongic acids) in the phosphatidylethanolamines (PE) and the attachment of identical acyl groups to the glycerol moiety. The biosynthesis and disposition of these unusual phospholipids were followed in the marine sponge Microciona prolifera where PE ( delta 5,9-26:2, delta 5,9-26:2) is a major molecular species. Incorporation experiments with radiolabeled fatty acids, bases, and intact phospholipids revealed the de novo biosynthesis of the two major phosphatides, phosphatidylethanolamines (PE) and phosphatidylcholines (PC), via the cytidine pathway as in higher animals, with ethanolamine selectively incorporated into PE( delta 5,9-26:2, delta 5,9-26:2). Methylation of PE and random acyl chain migration across different phospholipid classes were marginal, but the exchange of PC for PE, apparently mediated by the action of phospholipase, was indicated after uptake of the unnatural PC( delta 9-27:1, delta 9-26:1). The present study demonstrates in the most primitive multicellular animals a phospholipid metabolic pattern similar to that in higher organisms, with unique acyl and phosphoethanolamine transferases apparently involved in the biosynthesis of the (demospongic) di-C26-acyl-PE molecular species.