Acridine: a versatile heterocyclic nucleus.

Acridine is a heterocyclic nucleus. It plays an important role in various medicines. A number of therapeutic agents are based on acridine nucleus such as quinacrine (antimalarial), acriflavine and proflavine (antiseptics), ethacridine (abortifacient), amsacrine and nitracine (anticancer), and tacrine. Acridine is obtained from high boiling fraction of coal tar. It is also obtained in nature from plant and marine sources. Acridine undergoes a number of reactions such as nucleophilic addition, electrophilic substitution, oxidation, reduction, reductive alkylation and photoalkylation. The present review article summarizes the synthesis, reaction, literature review and pharmaceutical importance of acridine.

2,4,6-Trisubstituted pyrimidine derivatives as pregnancy interceptive agents.

A series of 2,4,6-trisubstituted pyrimidine derivatives was synthesized and evaluated for their in vivo pregnancy interceptive activity in hamsters. Out of the 17 compounds synthesized three compounds showed 100% activity at a dose of 10mg/kg.

Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist.

Herein we describe the chemical synthesis and pharmacological characterization of a novel, highly potent progesterone receptor (PR) antagonist, ZK 230211. The introduction of a 17alpha-pentafluorethyl side chain in the D-ring of the steroid skeleton allowed the combination of high antiprogestagenic activity with little or no other endocrinological effects. In contrast to many other antiprogestins, ZK 230211 did not convert to an agonist in the presence of protein kinase A (PKA) activators and showed high antiprogestagenic activity on both PR isoforms PR-A and PR-B. This high antiprogestagenic activity could also be demonstrated in several in vivo models. Furthermore, this compound displayed only marginal antiglucocorticoid effects. In tumor models ZK 230211 exhibited strong antiproliferative action. The pharmacological properties of ZK 230211 may prove useful in the treatment of endometriosis, leiomyomas, breast cancer, and in hormone replacement therapy.

[Effect of gonadotropin-releasing peptide (GRP) on LH secretion of mouse pituitary in vitro].

Synthetic GRP and its analogues, GRP-NH2, [Glu7.9.14 Lys6.10] GRP (6-14), [Phe14] GRP (5-14) and [Phe14] GRP, at the concentration of 0.05 mmol.L-1 were shown to have stimulatory effect on LH secretion in cultured mouse pituitary in vitro. The luteotropin releasing activity of GRP and its analogues was estimated to be 115.4, 114.2, 140.0, 162.0 and 179.0% of the control group, respectively. Subcutaneous administration of [Phe14] GRP on days 7-9 and 1-5 of pregnancy and [Phe14] GRP (5-14) on days 2-4 of gestation at dosage of 1 mg.d-1 (each mouse) caused fetal death in 40-60% of mice.

Syntheses and bioevaluation of substituted dihydropyridines for pregnancy-interceptive activity in hamsters.

A number of 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-substituted-1,4- dihydropyridines were synthesized and evaluated for pregnancy-interceptive activity in mated hamsters. Out of 24 compounds, 12, 15, 21, 22, 28, and 34 caused a marked reduction in the number of implantations when administered on days 3-8 postcoitum. In an in vitro competition assay, none of the compounds exhibited noticeable binding affinity for uterine progesterone receptors. The results reported here have helped to identify new leads for developing pregnancy-interceptive agents and the active compounds do not seem to elicit their interceptive effect through receptor-mediated inhibition of progesterone action in hamster uterus.

Synthesis and antifertility activity of zoapatanol analogues.

The synthesis of and guinea pig contragestational screening data for several oxepane and 3,8-dioxabicyclo[3.2.1]octane analogues of zoapatanol (1) are described and their structure-activity relationships discussed. Conversion of the 5-keto group on the nonenyl side chain of 1 into a hydroxyl function enhanced the potency. Further significant enhancement in the potency was realized with the transformation of several oxepanes into the 3,8-dioxabicyclo-[3.2.1]octane-1-acetic acid derivatives. Detailed, comparative contragestational evaluation of the three most potent compounds 9, 33, and 37 is presented, which led to the selection of 33 (ORF 13811) for further biological evaluation.

Synthesis and biological properties of 16(S)-amino-PGF2 alpha methyl ester.

A synthesis of 16-amino-derivatives of PGF2 alpha is reported. Introduction of an amino group into position 16 of PGF2 alpha has decreased the sensitivity of the compound to metabolic degradation. 16(S)-amino-PGF2 alpha methyl ester shows high abortifacient activity with reduced diarrhoeic side effect.

Synthesis of ent-17-(prop-1-ynyl-17 beta-hydroxy-11 beta-(4-(N,N-dimethylamino)-phenyl)-4,9-estradien-3-one, the antipode of RU-38 486.

The title compound was synthesized and tested for its biological activities. It showed neither antiprogesterone nor antiglucocorticoid properties.

A new class of nonhormonal pregnancy-terminating agents. Synthesis and contragestational activity of 3,5-diaryl-s-triazoles.

A series of 3,5-diaryl-s-triazoles were synthesized and evaluated as postimplantation contragestational agents. The introduction of various substituents (e.g., an o-alkyl chain on one phenyl and a m-alkoxy group on the other) was found to increase the potency. Several compounds with very high pregnancy-terminating activity in both hamsters and rats were obtained. One of these, 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-s-triazole, DL 111 (36), was selected for detailed evaluation in various animal species. A synthetic scheme for the preparation of these compounds and preliminary structure-activity relationships are presented.

Synthesis and antifertility activity of 13-aza 14-oxo-prostaglandins.

Some 13-aza-14-oxo prostaglandin analogues of PGF2 alpha, PGE2 and PGA2 have been synthetized in optically active form, starting from Corey's intermediate and evaluated for antifertility activity in the hamster. The C-15 absolute configuration was established and found critical for the biological activity, but unexpectedly the highest potency was always associated with the 15 epi derivatives. Among the PGF2 alpha analogues the 15 epi derivative was about one tenth as potent as PGF2 alpha. The preparation of a few 16-phenoxy 17,18,19,20 tetranor-derivatives led to more potent compounds with the p-fluorophenoxy analogue having the same potency as PGF2 alpha.

Synthesis and pregnancy terminating activity of 2-arylimidazo [2,1-a]isoquinolines and isoindoles.

A series of 2-arylimidazo[2,1-a]isoquinolines (1-21), some 5,6-dihydro derivatives (22-28) and 2-phenyl-5H-imidazol[2,1]isoindole (29) were synthesized and tested for the pregnancy terminating activity in hamsters and rats. An efficient preparation of 2-arylimidazo[2,1-a]isoquinolines was devised. The isoquinolines having a 4-chlorophenyl (8), 4-bromophenyl (9), or a biphenylyl group (12) in the 2-position were the most potent compounds after subcutaneous administration. Compound 12 also showed good oral activity. The data obtained with the title compounds are compared with those of the corresponding triazolo [5,1-1]isoquinolines and isoindoles. The structure-activity relationships are discussed.

2-(Aminomethyl)-2-decarboxyprostaglandin F2 alpha type analogs.

The 2-(aminomethyl)-2-decarboxy analogs of prostaglandin F2 alpha (PGF2 alpha), (15S)-15-methyl-PGF2 alpha, 16-phenoxy-omega-tetranor-PGF2 alpha and 16,16-dimethyl-PGF2 alpha were synthesized. The amino analogs closely resemble the parent PGF2 alpha compounds as antifertility agents in the hamster.

Synthesis and use of affinity-labeling steroids for interceptive purposes.

Synthesis of 17 beta-bromoacetoxy-19-nortestosterone was carried out by reaction of 19-nortestosterone with bromoacetic acid in the presence of dicyclohexycarbodiimide. The steroid was capable of alkylating cysteine, methionine, and histidine under physiologic conditions, indicating its potential as an affinity-labeling steroid. 17beta-Bromoacetoxy-19-nortestosterone interrupted postimplantation pregnancy in the rat when administered into the lumen of the uterus at low doses or subcutaneously at higher doses. Exogenous gonadotropins or steroids in dosages sufficient to maintain pregnancy do not prevent the interceptive action of this steroid. Animals whose first pregnancies were interrupted by this steroid had a subsequent normal pregnancy. The mode of action may be via covalent bonding to the progesterone receptor resulting in exclusion of endogenous progesterone.