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As part of the search for anti-trypanosomal agents, this work presents the production of sixteen derivatives. All of them were obtained from two natural diterpenes, one with kaurane skeleton (ent-kaurenoic acid) and other with a pimarane skeleton (ent-pimaradienoic acid). Then, the eighteen compounds were assayed against epimastigote form of Trypanosoma cruzi, with the derivatives showing increase of activity in relation to their precursors. Moreover, the most active derivative presented an IC50 50 = 9.8 µM), used as control. The esterification of acid diterpenes showed to be an interesting way in the search for anti-trypanosomal agents.

The search for new antibacterial agents and a better comprehension of substances with antimicrobial behavior is mandatory nowadays due to the serious public health problem of infection diseases. In the present work, 30 diterpenes were studied, with 2 natural derivatives, named ent-16-kauren-19-oic acid and ent-pimara-8(14),15-dien-19-oic acid, and 28 semi-synthetic derivatives. The natural diterpenes were isolated from Mikania glomerata and Viguiera arenaria, respectively. All diterpenes were submitted to antimicrobial assays against six different Gram-positive microorganisms to better understand the structure–activity relationship of antimicrobial diterpenes. The semi-synthetic derivatives were all obtained from the two natural derivatives by structural modifications, mainly esterification reactions. Both natural derivatives, together with the derivative ent-8(14)-pimaren-19-oic acid, displayed the most relevant antibacterial activities, with minimal inhibitory concentration (MIC) values that were less than 10 μg mL–1 for most pathogens; thus, they were considered promising antimicrobial agents. Moreover, in light of the hypothesis of Urzúa and colleagues, several considerations about the structure–activity relationship of antimicrobial diterpenes could be stated.

In this work, a search for antimicrobial agents against multi-drug resistant (MDR) bacteria was undertaken. It involved two natural diterpenes of different basic skeletons, named ent-kaurenoic acid and ent-pimaradienoic acid, that were used as precursors to access 28 semi-synthetic derivatives that were also submitted to biological assays. All 30 substances were assayed against a set of seven clinically isolated MDR bacteria, including three Staphylococcus aureus strains. Results classified both natural compounds as promising bactericidal antimicrobial agents against these MDR bacteria, especially for their performance in time-kill curve assay, improving on the positive control vancomycin. Moreover, di-hydro ent-pimaradienoic acid, obtained as one of the derivatives, also displayed promising minimum inhibitory concentration (MIC) values against the microorganism set, proving optimum activity against S. aureus strains. Thereby, this work also yielded a promising semi-synthetic bacteriostatic antimicrobial agent against MDR S. aureus. Furthermore, the study was carried out with 30 structures in order to verify the veracity and scope of Urzúa’s hypothesis about the structure-activity relationship between diterpenes and antimicrobial action. Our results are 93% in agreement with this hypothesis.

This paper presents a review on kaurane diterpenes, covering various aspects of chemical and microbiological transformations of native ent-kaurenoic acid, namely, its reactions via COOH groups, double bonds and rearrangements of the carbon skeleton that lead to a wide range of natural and synthetic derivatives with potential biologic activities and can present convenient synthons for the syntheses of other native ent-kauranes.

Alzheimer's disease is an irreversible, degenerative and age-related disease which is growing more and more with the increase in life expectancy. Kaurane diterpenes are a class of natural products available in large amounts in nature and isolated from plants grown worldwide. In the present work¸ twenty-seven kaurane diterpenes of natural origin and some readily available derivatives were assayed for acetylcholinesterase inhibition and the structure-activity relationship was analyzed. The kaurenoic acid derivatives screened showed to be promising inhibitors of AChE, which could provide new leads for drugs to fight Alzheimer's disease symptoms. Among them, eleven compounds showed activities comparable or higher than the positive control galantamine. Existence of an allylic hydroxyl group showed to be an important structural feature for AChE inhibition. In addition, presence of free hydroxyl groups at C-17 and C-19, furnished a diol especially active, able to completely inhibit AChE.

Polycyclization processes represent expeditious routes used in both nature and the laboratory to produce complex polycyclic molecules. A new stereoselective oxidative variant of such a polycyclization has been developed in which the cascade is triggered by a phenol dearomatization and is concluded by a pinacol transposition. This unprecedented avenue combines the synthetic power of a polycyclization and a transposition in tandem and enables the rapid formation of the tetracyclic main core of kaurane diterpenes containing several asymmetric and quaternary carbon centers in a single step from a simple phenol derivative.

This paper presents a review on kaurane diterpenes, covering various aspects of chemical and microbiological transformations of native ent-kaurenoic acid, namely, its reactions via COOH groups, double bonds and rearrangements of the carbon skeleton that lead to a wide range of natural and synthetic derivatives with potential biologic activities and can present convenient synthons for the syntheses of other native ent-kauranes.

A new kaurane diterpene dimer, 15-oxozoapatlin-13alpha-yl-10'alpha,16'alpha-dihydroxy-9'alpha-methyl-20'-nor-kauran-19'-oic acid gamma-lactone-17'-oate (1), together with the known 13-hydroxy-15-oxozoapatlin (2), 10alpha,13alpha,16alpha,17-tetrahydroxy-9alpha-methyl-15-oxo-20-nor-kauran-19-oic acid gamma-lactone (3), 2alpha,10alpha,13alpha,16alpha,17-pentahydroxy-9alpha-methyl-15-oxo-20-nor-kauran-19-oic acid (19,10)-lactone (4), 3alpha,10alpha,13alpha,16alpha,17-pentahydroxy-9alpha-methyl-15-oxo-20-nor-kauran-19-oic acid gamma-lactone (5), and 1beta,16alpha,17-trihydroxy-ent-kaurane (6) were isolated from the leaves of Parinari campestris and identified on the basis of detailed spectral analysis, including 2D NMR spectrometry and ESI-MS.

The new kaurane diterpene, ent-3β-butanoyloxykaur-15-en-17-ol, and four known kaurane diterpenes were isolated from the bulbs of Fritillaria ebeiensis. Their structures were elucidated on the basis of extensive spectroscopic analyses (IR, ESI-MS, HR-ESI-MS, 1-D and 2-D NMR). All the isolates showed neuroprotective effects against MPP(+)-induced neuronal cell death in human dopaminergic neuroblastoma SH-SY5Y cells.

SOUSA, Antonio Honório de. Estudo químico de Croton Limae A. P. S. Gomes, M. F. Sales & P. E. Berry (Euphorbiaceae). 2014. 279 f. Tese (Doutorado em química)- Universidade Federal do Ceará, Fortaleza-CE, 2014. The present work reports the chemical study related to the stem and the roots of Croton limae, collected in Andaraí/BA. The phytochemical investigation of ethanol extract from the stem lead to the isolation of two kaurane-type diterpenes, ent-kaur-16-en-18-oic acid and ent-kaur-16-en-15-oxo-18-oic acid, two clerodane-type diterpenes, 3,12-dioxo-15,16-epoxy-4α-hydroxycleroda-13(16),14-diene and 3-oxo-4α-hydroxy-13,14,15,16-tetranorclerodan-12-oic acid, and the flavonoid quercetin 3-O-β-D-glucopyranoside. The investigation of the hexane extract from the roots lead to the isolation of one triterpene, acetyl aleuritolic acid, the new dimer ent-17(α-pinen-10’-yl)-15-oxokauran-18-oic acid, two news clerodane diterpenes, 3-oxo-15,16-epoxy-4α,12-dihydroxycleroda-13(16),14-diene and 15,16-epoxy-3α,4α,12-trihydroxycleroda-13(16),14-diene, one halimane-type diterpene, 15,16-epoxy-3α,12-dihydroxyhalima-5(10),13(16),14-triene and the mixture of steroids β-sitosterol and stigmasterol. From the ethanol extract of the roots, it was possible to isolate the flavonoids kaempferol 3-O-β-glucopyranoside and ombuine 3-O-β-rutinoside and the three new clerodane diterpenes 3α,4α,15,16-tetrahydroxyclerod-13-ene, 6-(β-D-glucopyranosyl)-3,12-dioxo-15,16-epoxi-4α-hydroxycleroda-13(16),14-dieno and 3-oxo-4α,12-dihydroxy-14,15,16-trinorclerodan-13-oic acid. Four aromatic derivatives amides from ent-kaur-16-en-18-oic acid were prepared through nucleophilic substitutive reactions. The corresponding methyl esters from the ent-kaur-16-en-18-oic acid and ent-kaur-16-en-15-oxo-18-oic acid were also obtained. Two new derivatives from 3,12-dioxo-15,16-epoxi-4α-hidroxicleroda-13(16),14-dieno were prepared through reduction reaction and another one by the biotransformation of diterpene, made by the fungus Rhizopus stolonifer. Some isolated compounds and derivatives were submited to cytotoxic activity using ovarian (OVCAR-8), glioblastoma (SF-295) and colon (HCT-116) cell lines, and the compounds ent-kaur-16-en-15-oxo-18-oic acid and ent-17(α-pinen-10’-yl)-15-oxokauran-18-oic acid registered activity during preliminaries assays. The secondary metabolites were isolated through usual chromatography techniques, using thin layer chromatography, column chromatography, size exclusion chromatography and high performance liquid chromatography. The determination of the structure of the isolated compounds was performed through physical (melting point and optical rotation) and spectrometric techniques, such infrared (IR), high resolution mass spectrometry and nuclear magnetic resonance (NMR), including bidimensional experiments, and comparison with literature data. O presente trabalho relata o estudo químico do caule e das raízes de Croton limae, coletado no município de Andaraí-BA. A investigação fitoquímica do extrato etanólico do caule levou ao isolamento de dois diterpenos do tipo caurano, ácido ent-caur-16-en-18-oico e ácido ent-caur-16-en-15-oxo-18-oico, dois diterpenos do tipo clerodano, 3,12-dioxo-15,16-epoxi-4α-hidroxicleroda-13(16),14-dieno e ácido 3-oxo-4α-hidroxi-13,14,15,16-tetranorclerodan-12-oico, e do flavonoide 3-O-β-D-glicopiranosilquercetina. A investigação do extrato hexânico das raízes levou ao isolamento de um triterpeno, ácido acetilaleuritólico, do dímero inédito ácido ent-17(α-pinen-10’-il)-15-oxocauran-18-oico, de dois novos diterpenos clerodanos, 3-oxo-15,16-epoxi-4α,12-dihidroxicleroda-13(16),14-dieno e 15,16-epoxi-3α,4α,12-trihidroxicleroda-13(16),14-dieno, um diterpeno do tipo halimano, 15,16-epoxi-3α,12-dihidroxihalima-5(10),13(16),14-trieno, e da mistura dos esteroides β-sitosterol e estigmasterol. Do extrato etanólico das raízes foram isolados dois flavonoides, 3-O-β-D-glicopiranosilcanferol e ombuina-3-O-β-rutinosídeo, e três diterpenos clerodanos inéditos, 3α,4α,15,16-tetrahidroxicleroda-13-eno, 6-(β-D-glicopiranosil)-3,12-dioxo-15,16-epoxi-4α-hidroxicleroda-13(16),14-dieno e ácido 3-oxo-4α,12-dihidroxi-14,15,16-trinorclerodan-13-oico. Foram preparadas quatro amidas aromáticas derivadas do ácido ent-caur-16-en-18-oico e os respectivos ésteres metílicos dos ácidos ent-caur-16-en-18-oico e ent-caur-16-en-15-oxo-18-oico. Foram preparados dois derivados reacionais obtidos através de reações de redução do diterpeno clerodano 3,12-dioxo-15,16-epoxi-4α-hidroxicleroda-13(16),14-dieno e outro através da biotransformação deste diterpeno pelo fungo Rhizopus stolonifer. Alguns compostos isolados e derivados foram submetidos a testes de atividade citotóxica, utilizando linhagens de células tumorais de ovário (OVCAR-8), glioblastoma (SF-295) e colón (HCT-116), onde testes preliminares indicaram que os compostos ent-caur-16-en-15-oxo-18-oico e ácido ent-17(α-pinen-10’-il)-15-oxocauran-18-oico apresentaram atividade. Os metabólitos secundários foram isolados através de técnicas cromatográficas usuais, utilizando cromatografia em camada delgada, cromatografia em coluna, cromatografia por exclusão molecular e cromatografia líquida de alta eficiência. A determinação estrutural foi realizada através de métodos físicos (ponto de fusão e rotação óptica) e do uso de técnicas espectroscópicas e espectrométricas como infravermelho (IV), espectrometria de massas de alta resolução e ressonância magnética nuclear de hidrogênio (RMN 1H) e carbono-13 (RMN 13C), incluindo experimentos bidimensionais, além de comparação com dados da literatura.

Two new ent -kaurane diterpenes, 18,19-diacetoxy- ent -kaur-16-ene and 17-oxo- ent -kaur-15(16)-en-18-oic acid, were isolated from the aerial parts of Mikania banisteriae , together with the known ent -kauranes ent -kaur-16-en-18-oic acid and ent -kaur-16-en-18-ol. The structures were established by mass spectrometry, 1 H NMR and partly 13 C NMR spectroscopy. In addition, the sesquiterpene lactones eudesma-4(15),7(11)-dien-8β,12-olide and eudesma-4(15),7(11),8(9)-trien-12-olide as well as the sesquiterpenes 1β,6α-dihydroxyeudesm-4(15)-ene and caryophylleno-xide were identified by direct comparison (TLC, GC, GC-MS) with authentic samples. The chemotaxonomic significance is briefly discussed. ent -Kaur-16-en-18-oic acid and ent -kaur-16-en-19-oic acid showed no antifeedant, antimicrobial and antiinflammatory properties. © 1997 Elsevier Science Ltd. All rights reserved

A new trachylobane diterpene ent-trachyloban-18,19-diol (1) was isolated from root bark of Croton floribundus, along with known diterpenes ent-trachyloban-19-oic acid (2), 15b-hydroxy-ent-trachyloban-19-oic acid (3), ent-trachyloban-19-ol (4), ent-kaur-16-en- 19-oic acid (5), ent-kaur-16-ene-6a,19-diol (6) and ent-16a-hydroxykaur-11-en-19-oic acid (7). ent-trachyloban-18,19-diol (1) was submitted to derivatization reactions affording four new compounds (8-11). Cytotoxic activity of diterpenes 1, 3, 4, 7-11 against three human cancer cell lines was evaluated. No compounds showed cytotoxic potential with IC50 values greater than 25 mg/mL. Compound 6 was evaluated against five human cancer cell lines, showing moderate effect against three cancer cell lines, MDA-MB-435, HCT-8 and HCT-116, with IC50 values of 14.32, 13.47 and 12.1 mg/mL, respectively.

Coumarin (1) and kaurane-type diterpenes are considered the bioactive constituents of Mikania glomerata and M. laevigata, used in Brazil to treat respiratory affective disorders. The seasonal variation of 1, ortho-coumaric acid (2), benzoylgrandifloric acid (3), cinnamoylgrandifloric acid (4), and kaurenoic acid (5) in leaves of both species, cultivated in full sunlight and under shade levels of 40 and 80%, was quantified by HPLC. Compound 2 was detected solely in M. laevigata in concentrations below the limit of quantification. Coumarin was not found in M. glomerata, whereas its concentration reached 0.94±0.24% (w/w) in M. laevigata farmed in summer under 80% shading. Both Mikania species produced higher amounts of kaurane diterpenes when cultivated in plenty of sunlight. Hence, maximum contents of 1 are reached in M. laevigata cultivated under high shading, but with reduced concentrations of 3-5. Conversely, M. glomerata should be cultivated under full sunlight and harvested in winter for highest concentrations of kaurane-type diterpenes.

The MeOH-Et 2 O (1:1) extract of the aerial parts of Aster tongolensis gave one known (1) and three novel (2-4) kaurane diterpenoids. Structures were established by spectral analyses (ir, ms, 1 H and 13 C nmr) and chemical transformation. The taxonomic significance of kaurane diterpenes is discussed in brief

A monoterpene, 3beta,6beta-dihydroxy-p-menth-1-ene has been isolated from the seeds of Xylopia sericea along with four kaurane, one beyerene, one atisene and four trachylobane diterpenoids, including the trachyloban-18- and 19-methyl esters. The X-ray crystal structure of methyl ent-trachyloban-18-oate was determined in order to make an unambiguous distinction between the 18- and 19-esters. The 13C NMR data for ent-15alpha-hydroxy-trachyloban-19-oic acid has been revised.

The clinically used extract (TΠ) of Tripterygium wilfordii Hook f. give 19 new compounds, including five kaurane diterpenes (1–5), one manoyl oxide diterpene (6), and one abietane diterpene (7), three ursene triterpenes (8, 9 and 15), six oleanane triterpenes (10–13, 16 and 19), and three friedelane triterpenes (14, 17 and 18), as well as 15 known compounds (20–34). Their structures were elucidated by spectroscopy and X-ray analysis. Based on the screening of isolated compounds and other compounds reported in previous papers [J. Nat. Prod. 62 (1999) 1522; J. Nat. Prod. (2001) in press; Phytochemistry 53 (2000) 805], we identified the main components that are responsible for the therapeutic effect of TΠ.

Protein tyrosine phosphatase 1B (PTP1B) is considered as a therapeutic target for the treatment of diabetes and obesity. In our preliminary screening study, a MeOH extract of the aerial part of Siegesbeckia glabrescens was found to inhibit PTP1B activity at 30 microg/mL. Bioassay-guided fractionation led to the isolation of two active diterpenes, ent-16betaH, 17-isobutyryloxy-kauran-19-oic acid (1) and ent-16betaH, 17-acetoxy-18-isobutyryloxy-kauran-19-oic acid (2), along with ent- 16betaH, 17-hydroxykauran-19-oic acid (3). Compounds 1 and 2 inhibited the PTP1B activity with IC50 values of 8.7 +/- 0.9 and 30.6 +/- 2.1 microM, respectively. Kinetic studies suggest that both 1 and 2 are non-competitive inhibitors of PTP1B. However, compound 3 substituted with a hydroxyl group at C-17 in kaurane-type showed no inhibitory effects towards PTP1B.

From the acetone and ethanol extracts of the tubercula of Aristolochia pubescens, two diterpene esters of aristolochic acids were isolated, together with 23 known compounds. The structures of the compounds were determined on the basis of spectroscopic analysis.

Two bioactive pyranocoumarins 1 (sesselin) and 3 (xanthyletin) and one prenylated coumarin 2 (sub-erosin), beside three rare kaurene diterpenes 5-7 were isolated from the roots of Fortunella margarita. Their structures were determined from their spectroscopic data, including 1 H/ 13 C 2D NMR experiments. The kaurene diterpenes 5-7 are reported in Rutaceae for the first time. Diterpene 5 was found to be a potent stimulator of uterine contraction; it also caused stimulation of brain activity.

Xylopia frutescens is a tree native to the Brazilian Amazon whose seeds are rich in kaurenoic acid, a diterpene that showed in vitro activity against Trypanosoma cruzi. Aiming to find out alternative sources for kaurenoic acid, the content of some kaurane diterpenes was evaluated in X. aromatica and X. brasiliensis, species occurring in the Cerrado area of Minas Gerais, and also in X. frutescens. A reversed phase HPLC isocratic method was developed and validated to perform the assays. Kaurenoic acid was found to be the most abundant diterpene within the analyzed species, with a 3.16+/-0.97% content in the seeds of X. frutescens, which also presented the highest amount of xylopic acid (1.09+/-0.33%). The highest concentration of 16-alpha-hydroxykauranoic acid (1.96+/-1.58%) was found in the stems of X. aromatica.

From the aerial parts of Mikania vitifolia three new ent-kaurane diterpenes, ent-7α-cinnamoyloxy-15β-hydroxy-kaur-16-en-19-oic acid, ent-15β-cinnamoyloxy-7α-hydroxy-kaur-16-en-19-oic acid and ent-15β-hydroxy-7α-(E)-lachnophylloyloxy-kaur-16-en-19-oic acid were isolated together with the known ent-kauranesent-kaur-16-en-19-oic acid, ent-kaur-16-en-19-ol, ent-15β-hydroxy-kaur-16-en-19-oic acid and ent-15α-cinnamoyloxy-kaur-16-en-19-oic acid. The structures were established by mass spectrometry, 1H NMR and partly 13C NMR spectroscopy. Isolation of the new ent-7α-cinnamoyloxy-15β-hydroxy-kaur-16-en-19-oic acid (1), ent-15β-cinnamoyloxy-7α-hydroxy-kaur-16-en-19-oic acid (2) and ent-15β-hydroxy-7α-(E)-lachnophylloyloxy-kaur-16-en-19-oic acid (3) as well as further ent-kauranes. Institut für Pharmazeutische Chemie//IPC/Alemania Universität Düsseldorf//HHU/Alemania Universität Freiburg//ALU/Alemania Institut für Pharmazeutische Biologie//IPB/Alemania Instituto Nacional de Biodiversidad//INBio/Costa Rica UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Química

Two new diterpenes have been isolated from the twigs of Ryparosa acuminata ( Flacourtiaceae ), and identified as 16α,19-dihydroxykauran-20-oic acid δ- lactone and 16α-hydroxykaurane-19,20-dial. Friedelin and eudesmin were also isolated. The structure of the lactone was confirmed by X-ray crystallography.

The stem bark of Xylopia aethiopica has yielded four diterpenes, two of them novel. Three of the diterpenes were identified as (−)-kaur-16-en-19-oic acid and its 7-oxo and 7β-hydroxy derivatives. The fourth was the novel kolavane derivative 2-oxo-kolav-3,13-dien-15-oic acid, a type of compound not previously recorded in the Annonaceae.