Identification of degradants of a complex alkaloid using NMR cryoprobe technology and ACD/structure elucidator

Abstract

Identification of degradants of pharmaceuticals is a necessary challenge of the drug development process following the subjection of candidate molecules to a variety of physico-chemical stresses. It would be desirable to be able to conduct such studies on a minimal amount of material. As a prototypical study, the isolation and identification of degradants of a sample of the complex indoloquinoline alkaloid, cryptospirolepine, was undertaken after prolonged storage in DMSO solution using a combination of cryogenic NMR probe technology and CASE (Computer-Assisted Structure Elucidation) programs. None of the starting alkaloid remained after storage; a chromatogram of the DMSO solution demonstrated the presence of >25 components in the mixture. The two most abundant degradation products were identified as the known alkaloid cryptolepinone (~35%) and an unprecedented rearrangement product, DP-2, (~16%).

Current perspectives in drug discovery against tuberculosis from natural products

“…Excellent reviews on these topics are available [46,[152][153][154]. The major contributing factors in NMR are the superconducting magnet technology [155], micro-and cryoprobe technology [156][157][158], and the establishment of a myriad of multi-pulse experiments that cover all routine aspects of organic structure determination [159]. The need to analyze natural product quantities that are sufficient for the anti-TB bioassay (100 lg for a MABA anti-TB test) make sensitive 1 H NMR methods most useful for structural characterization of active compounds in a bioassay-guided drug discovery program.…”

The application of NMR-based metabonomics in neurological disorders

“…A critical development in overcoming this limitation has been the recent commercialization of NMR detectors (probes) cooled to near cryogenic temperatures, usually around 20 K, which improve the signal-to-noise ratio (SNR) via reduction of the thermal (Johnson) noise level by a factor proportional to the square root of the temperature ratio. 54 In practice, this results in an improvement of around 400% in sensitivity (for a single scan) and reduces the data acquisition time by ϳ16 fold. With the gain in SNR, the use of other less sensitive nuclei in biofluid analysis such as 13 C, 15 N, or 31 P becomes possible.…”

Structure elucidation of indole–indoline type alkaloids: A retrospective account from the point of view of current NMR and MS technology

“…A potentially useful utilization of these correlation data would be in computer assisted structure elucidation (CASE). CASE systems have recently arrived at a state of development so that they can significantly facilitate the structure elucidation of quite complicated alkaloid structures [104,105]. Although these developments have not yet been arrived to the point where unknown structures could be solved without human interference, they are a useful source of making structural propositions.…”