Structure-activity studies of 16-methoxy-16-methyl prostaglandins

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Pharmacology

Background:

• Prostaglandins (PGs) are lipid compounds with hormone-like effects.
• Modifications to prostaglandin structure can alter their biological activity.
• Understanding structure-activity relationships is key for developing targeted therapeutics.

Purpose of the Study:

• To synthesize pure diastereoisomers of 16-methoxy-16-methyl-PGF2α, -PGE2, and -PGE1.
• To evaluate the antisecretory, antifertility, and diarrheogenic effects of these synthetic prostaglandin analogues.
• To determine the critical role of C-15 and C-16 configurations in biological activities.

Main Methods:

• Stereoselective synthesis of prostaglandin analogues with specific C-16 substitutions.
• Establishment of absolute C-16 configuration using chemical methods.
• Tentative assignment of C-15 configurations based on chromatography and NMR spectroscopy.
• In vitro and in vivo evaluation of biological activities (antisecretory, antifertility, diarrheogenic).

Main Results:

• Successfully synthesized pure diastereoisomers of 16-methoxy-16-methyl-PGF2α, -PGE2, and -PGE1.
• Demonstrated that both C-15 and C-16 configurations are critical for observed biological activities.
• Showed that C-16 methyl and methoxy group introduction significantly improves the antisecretory to diarrheogenic action ratio.

Conclusions:

• The stereochemistry at C-15 and C-16 positions profoundly influences the pharmacological profile of prostaglandin analogues.
• The specific modifications at C-16 enhance desired antisecretory effects while mitigating undesirable diarrheogenic side effects.
• A specific PGE1 derivative (MDL 646, mexiprostil) with favorable properties was identified for further clinical investigation.