Absolute Configuration and Conformational Analysis of Brevipolides, Bioactive 5,6-Dihydro-α-pyrones from Hyptis brevipes

Abstract

The (6'S)-configuration of brevipolides A-J (1-10), isolated from Hyptis brevipes, was established by X-ray diffraction analysis of 9 in conjunction with Mosher's ester analysis of the tetrahydro derivative 11 obtained from both geometric isomers 8 and 9 as well as by chemical correlations. The structure of the new brevipolide J (10) was characterized through NMR and MS data as having the same 6-heptyl-5,6-dihydro-2H-pyran-2-one framework possessing the cyclopropane moiety of all brevipolides but substituted by an isoferuloyl group instead of the p-methoxycinnamoyl moiety found in 8 and 9. Conformational analysis of these cytotoxic 6-heptyl-5,6-dihydro-α-pyrones was carried out on compound 9 by application of a protocol based on comparison between experimental and DFT-calculated vicinal (1)H-(1)H NMR coupling constants. Molecular modeling was used to correlate minimum energy conformers and observed electronic circular dichroism transitions for the isomeric series of brevipolides. Compounds 7-10 exhibited moderate activity (ED(50) 0.3-8.0 μg/mL) against a variety of tumor cell lines.

Enantioselective synthesis of (+)-brevipolide H

“…1,2 The reported bioactivity of brevipolides includes inhibitory effects to chemokine receptor CCR5, 1 which is utilized by human immunodeficiency virus (HIV) to enter and infect host cells, 3 and cytotoxicity against cancer cell lines. 2,4 For example, brevipolide H (1) shows an average IC 50 = 5.6 μM against multiple cancer cell lines. 4 Brevipolides are highly functionalized molecules, whose 12-carbon skeleton comprises a 5,6-dihydro-α-pyrone, a cyclopropyl ketone and bears a mono-or di-oxygenated cinnamate group ( Figure 1).…”

“…2,4 For example, brevipolide H (1) shows an average IC 50 = 5.6 μM against multiple cancer cell lines. 4 Brevipolides are highly functionalized molecules, whose 12-carbon skeleton comprises a 5,6-dihydro-α-pyrone, a cyclopropyl ketone and bears a mono-or di-oxygenated cinnamate group ( Figure 1). All the brevipolides isolated so far have the same chirality centers.…”

“…5S,8R,9S,E)-9-((tert-Butyldimethylsilyl)oxy)-8-hydroxy-5-((4-methoxybenzyl)oxy)deca-1,6-dien-4-yl acrylate(4) Bromotrimethylsilane(176 mg, 1.15 mmol) was added dropwise to a solution of 14 (525.0 mg, 0.96 mmol) and dichloromethane (35.4 mL) at -30 o C. The mixture was stirred at -30 o C for 0.5 h, quenched with ice water (5 mL), and neutralized with sat. NaHCO 3(aq) to pH 7.…”

Abiotic factors influencing podophyllotoxin and yatein overproduction in Leptohyptis macrostachys cultivated in vitro

“…Previously chemical studies concerning Hyptis spp. describe the presence of aryltetralins lignans in different plant parts (Raffauf et al, 1987) and a set 6heptyl-5,6-dihydro-2H-2-one derivatives (Suárez-Ortiz et al, 2013).…”

Antiparasitic Metabolites from Hyptis brevipes, a Tacana Medicinal Plant

“…Our study, detailed in Scheme 1, represents the first work applying antiparasitic activity criteria to isolate the active metabolites from H. brevipes, we used Leishmania amazonensis strain for the bioguided isolation, since this parasite was the most labile and allowed the isolation of seven compounds, among them four brevipolides H (1, 0.58%), G (4, 0.13%), C (6, 1.17%), J (5, 0.11%); a catechol derivative (2, 0.66%); three flavonoids: chrysosplenol C (3, 0.08%), tomentin (7, 0.16%) and rutin (8, 0.07%), with different antiparasitic profiles, these were characterized by spectroscopic analyses, including NMR spectroscopy and MS spectrometry. Our data was compared with reported for these compounds [6,7,[12][13][14]. Biological results, for raw extract and pure compounds, are organized as IC 50 values in Table 1.…”