ABSTRACT
[formula: see text] The first chiral auxiliary mediated asymmetric synthesis of the naturally occurring Lycopodium alkaloid (+)-luciduline has been accomplished. Key steps include an IMDA reaction of a chiral dihydropyridine, a subsequent retro-Mannich ring opening, and a novel cationic reductive cyclization reaction.
Subject(s)
Plants, Medicinal/chemistry , Quinolines/chemical synthesis , Mannich Bases , StereoisomerismABSTRACT
A simple and general approach to the synthesis of chemical libraries based on a universal anhydride template allows the preparation of large number of compounds. Various cyclic/acyclic amines, primary/secondary amines, differentially protected bifunctional amines were used as nucleophiles to react with anhydrides. The free carboxylic acid generated was then coupled with solid-bound amines. The facile and rapid generation of compounds through this multi-component assembly can be accomplished in a combinatorial parallel synthesis.
Subject(s)
Amides/chemistry , Anhydrides/chemistry , Acylation , Amines/chemistry , Amino Acids/metabolism , Fluorenes/metabolism , Molecular Structure , Resins, PlantABSTRACT
A series of pseudopeptides containing alkyl-, cycloalkyl-, aryl-, and aralkyl-substituted 1,3,8-triazaspiro[4.5]decan-4-one-3-acetic acids as amino acid surrogates to replace the Pro2-Pro3-Gly4-Phe5 section of the peptide bradykinin B2 receptor antagonist [Pro3, Phe5]HOE 140 (D-Arg0-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-D-Tic7+ ++-Oic8-Arg9) were prepared. These psuedopeptides were examined in vitro for their B2 receptor affinities as well as for their ability to block bradykinin mediated actions in vivo. Two compounds in particular, NPC 18521 (I) and NPC 18688 (V) were quite potent in these latter assays, indicating that a significant portion of this prototypical second generation decapeptide antagonist can be replaced with a more compact nonpeptide molecule.
Subject(s)
Bradykinin Receptor Antagonists , Imidazoles/chemical synthesis , Spiro Compounds/chemical synthesis , Amino Acid Sequence , Animals , Binding, Competitive , Blood Pressure/drug effects , Bradykinin/antagonists & inhibitors , CHO Cells , Cell Membrane/drug effects , Cricetinae , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , Molecular Sequence Data , Molecular Structure , Oligopeptides/metabolism , Rabbits , Rats , Rats, Sprague-Dawley , Receptor, Bradykinin B2 , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
PURPOSE: Optimization of the therapeutic ratio of analogs of the topically active 11-cis, 13-cis-12-hydroxymethylretinoic acid, delta-lactone (1) relative to antihyperproliferation and antihyperkeratinization vs. toxicity. METHODS: Nine analogs of 1, in which variations were made in the lipophilic cyclohexenyl moiety or in the lactone ring, were evaluated for topical activity against hyperkeratinization, inhibition of TPA-induced DNA synthesis and for skin irritation. RESULTS: Although more potent lactones than the parent lactone 1 were identified, none possessed the favorable therapeutic ratio associated with 1. CONCLUSIONS: The delta-lactone 1 possesses unique molecular features responsible for its desirable therapeutic ratio as an antihyperproliferative and antihyperkeratotic agent. In view of its very low systemic retinoid toxicity and the absence of any systemic toxicity, this lactone may be a good candidate for use in the topical treatment of acne.
Subject(s)
Lactones/pharmacology , Retinoids/pharmacology , Skin Diseases/drug therapy , Administration, Topical , Animals , Drug Evaluation, Preclinical , Keratins/metabolism , Lactones/chemical synthesis , Lactones/toxicity , Mice , Retinoids/chemical synthesis , Retinoids/toxicity , Skin/drug effects , Skin/metabolism , Skin Diseases/metabolism , Tretinoin/pharmacologySubject(s)
Lactones/pharmacology , Skin/drug effects , Tretinoin/pharmacology , Administration, Topical , Animals , Cell Division/drug effects , DNA/biosynthesis , DNA/drug effects , Female , Keratosis/prevention & control , Lactones/chemistry , Mice , Ornithine Decarboxylase Inhibitors , Skin/enzymology , Structure-Activity Relationship , Tretinoin/chemistryABSTRACT
A series of 2-benzylsuccinimides (4a-f) were prepared for evaluation as potential anticonvulsants. Primary (Phase I) screening of these compounds indicated that succinimides 4d and 4e, containing lipophilic (+ pi), electron-withdrawing (+ sigma) phenyl substituents, were the most effective in controlling seizures induced by maximal electroshock (MES) and subcutaneous pentylenetetrazol (scMet). Compounds 4a, 4c, and 4d showed activity against scMet-induced seizures equal to that of their 2-phenylsuccinimide analogues and were somewhat more effective in the MES test. In quantitative (Phase II) testing, when administered ip in mice, 4d and 4e both demonstrated anticonvulsant potency superior to that of the prototype drug (ethosuximide) by the MES and scMet assays. However, they also exhibited greater neurotoxicity than ethosuximide in the rotorod test.
Subject(s)
Anticonvulsants/chemical synthesis , Succinimides/chemical synthesis , Animals , Anticonvulsants/pharmacology , Anticonvulsants/toxicity , Chemical Phenomena , Chemistry, Physical , Electroshock , Ethosuximide/pharmacology , Male , Mice , Pentylenetetrazole/antagonists & inhibitors , Postural Balance/drug effects , Succinimides/pharmacology , Succinimides/toxicityABSTRACT
A series of 2-benzylglutarimides (4) and their N-methyl analogues (5) were prepared according to the Topliss scheme for the selection of benzyl substituents to maximize anticonvulsant activity. A total of 22 such compounds were subjected to initial (phase I) screening in mice against seizures induced by maximal electroshock (MES) and pentylenetetrazol (scMet) and in the rotorod assay for neurotoxicity. From this series of test compounds, 10 were advanced to quantitative (phase II) testing. Of these, 2-(4-chlorobenzyl)glutarimide (4b) emerged as the most promising anticonvulsant drug candidate by demonstrating both good anti-scMet and anti-MES activity combined with low neurotoxicity after intraperitoneal administration in mice. In drug differentiation tests, 4b was also effective in nontoxic doses against seizures induced by bicuculline, picrotoxin, and strychnine. When compared with the clinically useful drugs phenytoin, carbamazepine, phenobarbital, valproate, and ethosuximide, 4b exhibited an overall pharmacological profile most closely resembling that of valproate.
