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Arzneimittelforschung 2003; 53(2): 73-79
DOI: 10.1055/s-0031-1297075
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Synthesis and Biological Evaluation of 16β-Pyrrolidinosteroidal Derivatives

Dharam Paul Jindal
a   University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
,
Poonam Piplani
a   University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
,
Hassan Fajrak
b   Department of Physiology and Pharmacology, Royal College, University of Strathclyde, Glasgow, Scotland, United Kingdom
,
Chris Prior
b   Department of Physiology and Pharmacology, Royal College, University of Strathclyde, Glasgow, Scotland, United Kingdom
,
Ian G. Marshall
b   Department of Physiology and Pharmacology, Royal College, University of Strathclyde, Glasgow, Scotland, United Kingdom
› Author Affiliations
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Publication History

Publication Date:
25 December 2011 (online)

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Summary

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.

Zusammenfassung

Synthese und biologische Evaluierung 16-Beta-pyrrolidino-steroider Derivate In der vorliegenden Studie werden die Synthese einiger steroider bisquaternärer Ammonium-Verbindungen (Verbindungen 10 und 11) sowie ihre neuromuskulär blockierende Wirkung in vitro und in vivo beschrieben. Die Pyrrolidin-Gruppe wurde sowohl an der 3-Betaals auch der 16-Beta-Position des steroiden Nukleus inkorporiert, um die Relevanz der Interoniumsdistanz zwischen den zwei quaternären Ammoniumzentren zu untersuchen. Die 16-Beta-pyrrolidinomonoquaternäre Derivate ( Verbindungen 14, 15, und 16) wurden ebenfalls synthetisiert. In In-vivo-Studien erwies sich das 17-beta-acetoxische bisquaternäre Derivat (Verbindung 11) als potenter als d-Tubocurarin (CAS 57-94-3). Das 17-Beta-hydroxy-bisquaternäre Derivat ( Verbindung 10) und sein 16-Beta-pyrrolidino-monoquaternärer Partner ( Verbindung 15) stellten sich im Vergleich zu d-Tubocurarin in In-vitro-Studien als weniger aktiv heraus. Die 16-Beta-Pyrrolidino-monoquaternären Verbindungen 14 und 16 wurden aufgrund ihrer problematischen Löslichkeit nicht geprüft. Die Zwischensubstanz (Verbindung 12) wurde vom National Cancer Institute (NCI), Bethesda (USA) für weitere Untersuchungen auf antineoplastische Aktivität ausgewählt, erwies sich jedoch als inaktiv.

Key words

Ammonium derivatives, bisquaternary, monoquaternary - CAS 57-94-3 - 16β-Pyrrolidinosteroidal derivatives, biological evaluation, synthesis - d-Tubocurarine