Robert T. Blickenstaff

Synthesis of steroidal cyclophosphamides

The Reformatsky product of estrone methyl ether and ethyl bromo-acetate was transformed by two separate routes to 21-amino-3-methoxy-17alpha-pregna-1,3,5(10)-trien-17beta-ol (9). Cyclization with bis- (2-chloroethyl) phosphoramide dichloride produced the steroidal cyclophosphamide 10. Analogous syntheses transformed androstenolone into steroidal cyclophosphamide 20 and androstenedione into steroidal cyclophosphamide 28.

Synthesis of some analogs of estradiol.

As part of a search for estradiol derivatives designed for conjugation to carboxyl or amine functions of anti-cancer agents or suitable derivatives thereof, estradiol analogs with side chains at the C-16 or -17 position were prepared for biological assay. These analogs include several which have a substituted nitrogenous function at C-17. The avidity of some of these analogs for binding to estrogen receptor was found to be of a low order.

Potential radioprotective agents—VI. Chalcones, benzophenones, acid hydrazides, nitro amines and chloro compounds. radioprotection of murine intestinal stem cells

There is an interest and need for new compounds that protect tissues from radiation injury. In cancer therapy, the protection of normal tissue without protecting tumors is one way to increase the therapeutic gain. Thiol compounds are currently in clinical trials, but are limited to some extent by their human toxicities including hypotension, nausea, and emesis. Several new aminochalcones and aminobenzophenones were synthesized and tested for radioprotective activity in mice. All were less active than p-aminobenzophenone itself. Several acid hydrazides were synthesized and tested similarly, but none exhibited significant activity. The high radioprotective activity of 4-nitroaniline was confirmed, but other nitro amines were substantially less active. 4-Chloro-N-methylaniline is as active as 4-chloroaniline, but other chloro aromatics are devoid of significant activity. When compared with the phosphorothioate amyfostine (WR-2721) using the intestinal clonogenic cell survival assay, 1-(p-aminophenyl)-1-propanol (15), p-aminopropiophenone (16), its ethylene ketal (14), and a mixture of the two (17) protected to a great extent, though slightly less than WR-2721. These results suggest that there is direct cellular radioprotection by these non-thiol compounds. The studies further suggest that preclinical toxicity testing of the most protective agents is warranted.

The anticoagulant effect of hexolame, N-(3-hydroxy-1,3,5(10)-estratrien-17β-yl)-6-hydroxyhexylamine, another amino-estrogen with prolonged anticoagulant effect

The anticoagulant and estrogenic effects of hexolame, N-(3-hydroxy-1,3,5(10)-estratrien-17 beta-yl)-6-hydroxyhexylamine, are described. A single subcutaneous injection of hexolame in adult and infant male mice produced dose-dependent increases in blood clotting time which could be observed even after 2 days. In ovariectomized mice, hexolame produced vaginal cornification (estrogenic response). The data suggested that if used in the treatment of prostatic cancer, hexolame, like prolame, would not induce cardiovascular accidents. It could also be useful in the prevention of thrombosis.

Potential radioprotective agents—V. Melatonin analogs. Oral activity of p-Aminopropiophenone and its ethylene ketal

Seven new amides of 5-methoxytryptamine were synthesized and tested for radioprotective activity in mice. One of them, the heptafluorobutyramide 4, is moderately active (57% survivors), the rest demonstrate little or no activity. Of twelve compounds that had been found to exhibit high radioprotective activity by ip injection, only two [p-aminopropiophenone (9) and its ethylene ketal 8] retain that high activity (92-95% survivors) when administered orally. Three are moderately active: p-aminobenzonitrile (10, 55%), 5-methoxytryptamine octanoic amide (11, 50%), and p-aminobenzophenone (12, 48%).

Synthesis and androgen receptor binding of dihydrotestosterone hemisuccinate homologs

Dihydrotestosterone-succinyl-agarose is the most common form of androgen affinity column. To investigate the effect of variation in the number of methylene groups between the ester and amide functions, a homologous series, varying the number of methylenes between the functional groups, has been synthesized and evaluated. In addition, since structure studies show 17 alpha-methyldihydrotestosterone binds with high affinity, a 17 alpha-carboxymethyl ligand (3) was studied. Relative binding affinities of the dicarboxylates (assayed as the n-butyl amides) range from 0.003 to 0.044 (dihydrotestosterone = 1.00), while there was no detectable binding for 3. Only the suberate binds better than the much-used succinate, and it would be a likely candidate for an affinity ligand.

Potential radioprotective agents — IV. Schiff bases

Twelve Schiff bases were prepared using salicylaldehyde, one with 5-chlorosalicylaldehyde, one with benzaldehyde, and a series of anilines substituted in the m- or p-positions. They were assayed for radioprotective activity in male, Swiss mice irradiated with a nearly lethal dose (950 cGy) of 6 mV photons produced by a linear accelerator, and were compared with the parent amines. Schiff base formation reduced toxicity of the parent amines; its effect on radioprotective activity was erratic, increasing activity in some cases, decreasing activity in others, and having no effect in still others. Radioprotective activity appears to be unrelated to a number of molecular descriptors. The highest radioprotection (100%) was observed for mixtures of p-aminopropiophenone with its Schiff base, or with the Schiff base of 1-(p-aminophenyl)-1-propanol (95%).

Total synthesis of diazasteroids

Abstract Contrary to previous reports, the condensation product of 8-aminoquinoline and 2-carbethoxycyclopentanone undergoes ring closure with polyphosphoric acid to give the 1,11-diazasteroid . Catalytic hydrogenation reduced the A ring and the double bond to produce . 8-Aminotetrahydroquinoline and 3-carbethoxy-2-piperidone condense to a tricyclic intermediate , which could not be cyclized to a steroid, however.

Intramolecular catalysi's. vii. The nature of side chain shielding of the 12α-Hydroxyl group of steroids ☆

Abstract A series of 12α-hydroxy steroids with varying side chains was prepared, and their 24-hour acetylation yields were compared, l2α-Hydroxy-5β-pregnan-20-one ( lb ) was prepared from 3α, 12α-diacetoxy-5β~pregnan-20-one ( 2 ) and also by side chain degradation of 12α-acetoxy-5β-cholanoic acid ( 5d ). 21-Benzyl-5β-pregnan-12α-ol ( 1g ) was synthesized by hydrogenation of the 21-benzylidine derivative of ketone 1b . 23-Pheny1-5β-norcholan-12α-ol ( 1k ) was obtained by the Grignard reaction of 2-phenyl-ethylmagnesium bromide and ketone 1b , dehydration, hydrogenation and hydride reduction; a similar sequence produced 20-methyl-5β-pregnan-12α-ol ( lm ). The acetylation results (Table 11) imply that branching at C-20 may be more significant for 12α-hydroxyl reactivity than side chain length or type. An additional compound with an unbranched side chain, 21-nor-5β-cholan-12α-ol ( 14 ), was synthesized by a Grignard reaction on the 21-bromo intermediate 11b . Acetylation rates determined by glc indicate (Table 111) That compounds with unbranched side chains have 12α-hydroxyl groups about ten times as reactive as their analogs with 20-methyl groups.

Intramolecular catalysis. IV A radioisotope method for determining rates of acetylation of hydroxy steroids

A method is described for determining the rates of acetylation of hydroxy steroids utilizing 14C-acetic anhydride. Applied to methyl 3α-, 7α-, and 12α-hydroxycholanates the method gave relative rate constants of 97, 1.0, and 1.5, respectively.