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Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, and other important diseases. Here, we report the inhibitory activity of a series of 76 dihydro-beta-agarofuran sesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter, to establish quantitative comparisons of their respective abilities to block the drug transport activity. The screening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulation of the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity and guide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The most salient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions, which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.

Calea urticifolia (Asteraceae: Asteroideae) has long been used as a traditional medicine in El Salvador to treat arthritis and fever, among other illnesses. The chloroform extract of the leaves of C. urticifolia showed potent inhibition of recombinant human monoamine oxidases (MAO-A and -B). Further bioassay-guided fractionation led to the isolation of a flavonoid, acacetin, as the most prominent MAO inhibitory constituent, with IC values of 121 and 49 nM for MAO-A and -B, respectively. The potency of MAO inhibition by acacetin was >5-fold higher for MAO-A (0.121 μM vs 0.640 μM) and >22-fold higher for MAO-B (0.049 μM vs 1.12 μM) as compared to apigenin, the closest flavone structural analogue. Interaction and binding characteristics of acacetin with MAO-A and -B were determined by enzyme-kinetic assays, enzyme-inhibitor complex binding, equilibrium-dialysis dissociation analyses, and computation analysis. Follow-up studies showed reversible binding of acacetin with human MAO-A and -B, resulting in competitive inhibition. Acacetin showed more preference toward MAO-B than to MAO-A, suggesting its potential for eliciting selective pharmacological effects that might be useful in the treatment of neurological and psychiatric disorders. In addition, the binding modes of acacetin at the enzymatic site of MAO-A and -B were predicted through molecular modeling algorithms, illustrating the high importance of ligand interaction with negative and positive free energy regions of the enzyme active site.

Two new sesquiterpenoids (1 and 2) with a dihydro-beta-agarofuran skeleton were isolated from Crossopetalum tonduzii. Their structures were elucidated on the basis of spectral analysis, including homonuclear and heteronuclear correlation NMR experiments (COSY, ROESY, HSQC, and HMBC). Their absolute configurations were determined by CD studies on 3, the benzoylated derivative of 1. Chemical correlations have allowed the absolute configurations of 4 and 5, two previously known dihydro-beta-agarofuran analogues, to be reported for the first time. Compounds 1, 2, and 5 showed strong antitumor-promoting effects on Epstein-Barr virus early antigen (EBV-EA) activation.

Six dihydro-P-agarofuran [5,11 -epoxy-5P,1 O~-eudesm-4(14) -ene] sesquiterpenes with a novel substitution pattern were isolated from Maytenus magellanica and their structures were elucidated by means of l H and 13C NMR spectroscopic studies, including lH-13C heteronuclear correlation (H ETCOR), long range correlation spectra with inverse detection ( H M BC) and NOE experiments. Their absolute configurations were determined by application of the CD exciton chirality method while hydrolysis and preparation of derivatives provided additional information. One of the sesquiterpenes exhibited sign if icant antif eeda nt activity against Spoduptera littoralis.As part of an intensive course of research into biologically active metabolites from Celastraceae species used in folk medicine, '-' Maytenus magellanica Hook was studied. This species grows in the phytogeographical region of the Antarctic forest (Argentina and Chile) and had shown moderate activity (LCs0 650 ppm) in the brine shrimp lethality b i ~a s s a y . ~Compound 1 showed antifeedant activity against Spodoptera littoralis in an election test, although it was not particularly effective against microorganisms 6*t or viruses.$The six metabolites isolated displayed a hitherto unreported substitution pattern on a dihydro-P-agarofuran [5,l l-epoxy-5~,lO~-eudesm-4( 14)ene] skeleton with la, 2p, 3P, 4p and 9P substituents. Four of the compounds also had substituents at 6p. The compounds closest in structure to them are those isolated by Kupchan from other Celastraceae: maytolin and maytolidin, with the basic polyhydroxy skeleton of maytol (la,2a,3P,4P,6P,9~,15-heptahydroxydihydro-P-agarofuran); they are also related to the sesquiterpene core of the macrocyclic alkaloids evonino1,8 euonyminol and isoeuonyminol. 'Regrettably, the absolute configurations of dihydro-p-agarofuran sesquiterpenes have not been reported. Clardy,' applying X-ray diffraction techniques to a celorbicol derivative with a heavy atom, gave the absolute configuration of a series of celorbicol derivatives; contradictory results were published regarding the determination of the absolute configuration of malkanguniol l 2 although the later corrections l 3 agreed in the main with the findings of Clardy. This paper gives an account of the structural elucidation of compounds 1, 4, 7, 9, 10 and 11 and their absolute configuration based on C D techniques and chemical correlations (Schemes 1 and 2). DiscussionThe molecular formula of compound 1 [u]k0 + 18.0 lo-' deg TCompound 1 was assayed on Staphylococcus aureus ATCC 6538, Bacillus subtilis CECT 39, Escherichia coli CECT 99, Salmonella sp. CECT 456, Saccharomyces cerevisiae X 2180 A, Candida albicans and Pseudomonas aeruginosa (from the Dept. of Microbiology of the University of Vancouver, BC). $ Herpes simplex virus Type 1, KOS strain (HSV-l), Vesicular Stomatitis Virus, Indiana strain (VSV) and HeLa (uterus neck cancer) cells were used.

The new sesquiterpene pyridine alkaloids chiapenines ES-I (1), ES-II (2), ES-III (3), and ES-IV (4), in addition to the known alkaloids wilfordine (5), alatamine (6), wilforidine (7), alatusinine (8), euonine (9), euonymine (10), ebenifoline E-I (11), forrestine (12), mayteine (13), and 4-hydroxy-7-epi-chuchuhuanine E-V (14), were isolated from the leaves of Maytenus chiapensis. Their structures were elucidated by 1D and 2D NMR spectroscopy, including homonuclear and heteronuclear correlation (COSY, ROESY, HSQC, and HMBC) experiments. Wilfordine, alatusinine, and euonine exhibited strong antifeedant activity against Spodoptera littoralis.

Five new lupane triterpenes (1-5), in addition to 24 known ones, were isolated from Maytenus cuzcoina and M. chiapensis. Their structures were elucidated on the basis of spectroscopic analysis, including homonuclear and heteronuclear correlation NMR (COSY, ROESY, HSQC, and HMBC) experiments. The compounds were assayed for antimicrobial and cytotoxic activities, with 3-epi-betulinic acid and 28,30-dihydroxy-3-oxolup-20(29)-ene showing moderate cytotoxicity.

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