Alkaloids and diarylheptanoids of hippobroma longiflora and pellacalyx saccardianus: structure and bioactivity

Chan, Zi-Yang (2021) Alkaloids and diarylheptanoids of hippobroma longiflora and pellacalyx saccardianus: structure and bioactivity. PhD thesis, University of Nottingham.

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Abstract

Plant secondary metabolites such as alkaloids and diarylheptanoids play a crucial role in drug discovery due to their high structural diversity and useful biological activity. The present research aims to isolate and elucidate bioactive alkaloids and/or diarylheptanoids from two understudied Malaysian angiosperms, i.e., Hippobroma longiflora (L.). G. Don. (Campanulaceae) and Pellacalyx saccardianus Scort. (Rhizophoraceae). H. longiflora is a naturalised herb with ethnobotany suggestive of neuroactive alkaloids, while P. saccardianus is a rainforest tree that exhibited remarkable cytotoxic activity.

Phytochemical investigation into the whole plant of H. longiflora yielded three new diphenethylpiperidine alkaloids, hippofoline A (1), hippofoline B (2) and (–)-cis-2′,2′′-diphenyllobelidiol N-oxide (5), along with two known alkaloids (–)-lobeline (3) and (–)-cis-2′,2′′-diphenyllobelidiol (4). The absolute configurations of alkaloid 1 and 2 were established based on experimental and calculated ECD data, while those of 3 and 4 were confirmed by X-ray crystallography. Alkaloids 2 – 4 were shown to induce concentration-dependent relaxation effects on rat isolated tracheal segments that were pre-contracted with carbachol, with 3 being especially potent (EC50 1.2 ± 0.2 nM). The antispasmodic activity of alkaloids 2 – 4 was postulated to involve the antagonism of muscarinic acetylcholine receptors. This novel pharmacological aspect justifies the diphenethylpiperidine alkaloids as antispasmodic drug leads.

From the leaves and bark of P. saccardianus, seven new nortropane alkaloids were characterised, i.e., 3α-cinnamoyloxy-N-phloretoylnortropane (6), 3α-cinnamoyloxy-N-formylnortropane (7), 3α-phenylacetoxy-N-formylnortropane (8), 3α-benzoyloxy-N-formylnortropane (9), 3α-acetoxy-N-formylnortropane (10), (±)-bissaccardine (13) and (±)-trissaccardine (14). Their chemical structures (including the relative configuration of 13) were elucidated by comprehensive spectroscopic analyses. Two known nortropane alkaloids, 3α-cinnamoyloxynortropane (11) and 3α-benzoyloxynortropane (12), were co-isolated in high yields. Through semi-synthesis experiments, the novel oligomers 13 and 14 were deduced to be natural aza-Michael adducts of the monomer 11. Alkaloids 13 and 14 also exhibited potent cytotoxicity towards a panel of pancreatic cancer cell lines (AsPC-1, SW1990, BxPC-3 and PanC-1), with IC50 values ranging from 1.13 – 10.85 μM. The unprecedented discovery of the cytotoxic tropane alkaloids 13 and 14 was highlighted. Additionally, alkaloids 6, 9, and 11 – 13 were shown to induce weak relaxation effects on rat isolated tracheal rings that were pre-contracted with carbachol. Analyses of their structure activity relationships with respect to antimuscarinic activity (atropine as positive control) suggested plausible weak receptor-binding interactions that may diminish antispasmodic activity.

On the other hand, two pairs of enantiomeric diarylheptanoid-phenylpropanoid adducts bearing a cyclohexenone core, (±)-saccardianones A and B (15 and 16), an alkaloidal diarylheptanoid-phenylpropanoid adduct bearing a 4-piperidone core (±)-saccardianine A (17), a pair of enantiomeric dimeric diarylheptanoid alkaloids bearing a tetrahydropyridine core, (±)-saccardianine B (18), a suspected degradation product, saccardianine C (19), together with a diarylheptanoid derived spirocompound, pellaspirone (20), and a diarylheptanoid-rutinoside, saccardianoside (21) were obtained and characterised from the leaves of P. saccardianus. Two known diarylheptanoids, platyphyllenone (22) and (±)-5-hydroxy-1,7-bis-(4-hydroxyphenyl)-3-heptanone (23) were co-isolated in high yields. The relative configuration of 15 was elucidated by X-ray crystallography, while that of 18 was determined by NOESY analysis. The absolute configuration of 21 was determined by chemical derivatisation coupled to HPLC and spectroscopic analyses. Through semi-synthesis experiment, 20 was deduced to be an experimental artifact. The biogenetic pathways of 15 – 18 were proposed with 23 as a common precursor, which underwent aldol condensation and/or transamination steps to afford the novel alicyclic cores. Compounds 16 and 20 exhibited moderate but selective cytotoxicity towards pancreatic AsPC-1 (IC50 15.47 μM) and breast MDA-MB-231 (IC50 13.32 μM) cancer cell lines, respectively.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Lim, Kuan Hon
Ting, Kang Nee
Keywords: alkaloids; lobeline; tropane; diarylheptanoids; hippobroma longiflora; pellacalyx saccardianus; antispasmodic; cytotoxic
Subjects: R Medicine > RC Internal medicine
Faculties/Schools: University of Nottingham, Malaysia > Faculty of Science and Engineering — Science > School of Pharmacy
Item ID: 64628
Depositing User: Chan, Zi-Yang
Date Deposited: 04 Aug 2021 04:40
Last Modified: 04 Aug 2021 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/64628

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