Absolute configuration assignment to anticancer Amaryllidaceae alkaloid jonquailine

Area of Science:

• Natural Product Chemistry
• Computational Chemistry
• Medicinal Chemistry

Background:

• Jonquailine is a novel alkaloid isolated from Narcissus jonquilla.
• It demonstrates significant anti-proliferative activity against various cancer cell types.
• The stereochemistry at C-8 of the B ring is linked to its activity, but the absolute configuration was unknown.

Purpose of the Study:

• To determine the absolute configuration of jonquailine.
• To extend this determination to related analogues, pretazettine and 8-O-methylpretazettine.
• To evaluate the utility of different chiroptical methods in configuration assignment.

Main Methods:

• Density Functional Theory (DFT) calculations were employed.
• Chiroptical properties including electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and optical rotatory dispersion (ORD) were computed.
• Calculated properties were used to assign the absolute configuration.

Main Results:

• Vibrational circular dichroism (VCD) proved to be the most effective method for assigning the absolute configuration.
• Electronic circular dichroism (ECD) was not sufficiently discriminating for this purpose.
• Optical rotatory dispersion (ORD) provided limited utility in the configuration assignment.

Conclusions:

• The absolute configuration of jonquailine has been successfully assigned using DFT calculations, with VCD being the decisive method.
• This methodology provides a reliable approach for determining the absolute configuration of jonquailine analogues.
• The findings contribute to understanding the structure-activity relationship of jonquailine in cancer therapy.