Synthesis and biological evaluation of 16 beta-pyrrolidinosteroidal derivatives.
The synthesis of some steroidal bisquaternary ammonium substances (compounds 10 and 11), and their in vitro and in vivo neuromuscular blocking action are described in this report. The pyrrolidino functionality was incorporated at both the 3-beta and 16-beta positions of the steroid nucleus to study the importance of the interonium distance between the two quaternary ammonium heads. The 16-beta-pyrrolidino monoquaternary derivatives (compounds 14, 15, 16) were also prepared. The 17-beta-acetoxy bisquaternary derivative compound 11 was found to be more potent than d-tubocurarine (CAS 57-94-3) in in vivo studies. The 17-beta-hydroxy bisquaternary derivative, compound 10, and its 16-beta-pyrrolidino monoquaternary partner, compound 15, were found to be less active as compared to d-tubocurarine in in vitro studies. The monoquaternary compounds 14 and 16 were not tested due to their solubility problems. The intermediate substance, compound 12 was selected by the National Cancer Institute (NCI), Bethesda (USA) for investigation for antineoplastic activity but was found to be inactive.
Jindal
Dharam Paul
DP
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. dharampjindal@yahoo.co.in
Piplani
Poonam
P
Fajrak
Hassan
H
Prior
Chris
C
Marshall
Ian G
IG
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D007202:Indicators and Reagents; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects; D009466:Neuromuscular Blocking Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013260:Steroids, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014403:Tubocurarine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
C472886:16-pyrrolidinosteroid; D007202:Indicators and Reagents; D009466:Neuromuscular Blocking Agents; D003473:Neuromuscular Nondepolarizing Agents; D011978:Receptors, Nicotinic; D013260:Steroids, Heterocyclic; D000109:Acetylcholine; D014403:Tubocurarine