We assembled new plastomes of 19 species of Mikania and of Ageratina fastigiata, Litothamnus nitidus, and Stevia collina, all belonging to tribe Eupatorieae (Asteraceae). We analyzed the structure and content of the assembled plastomes and used the newly generated sequences to infer phylogenetic relationships and study the effects of different data partitions and inference methods on the topologies. Most phylogenetic studies with plastomes ignore that processes like recombination and biparental inheritance can occur in this organelle, using the whole genome as a single locus. Our study sought to compare this approach with multispecies coalescent methods that assume that different parts of the genome evolve at different rates. We found that the overall gene content, structure, and orientation are very conserved in all plastomes of the studied species. As observed in other Asteraceae, the 22 plastomes assembled here contain two nested inversions in the LSC region. The plastomes show similar length and the same gene content. The two most variable regions within Mikania are rpl32-ndhF and rpl16-rps3, while the three genes with the highest percentage of variable sites are ycf1, rpoA, and psbT. We generated six phylogenetic trees using concatenated maximum likelihood and multispecies coalescent methods and three data partitions: coding and non-coding sequences and both combined. All trees strongly support that the sampled Mikania species form a monophyletic group, which is further subdivided into three clades. The internal relationships within each clade are sensitive to the data partitioning and inference methods employed. The trees resulting from concatenated analysis are more similar among each other than to the correspondent tree generated with the same data partition but a different method. The multispecies coalescent analysis indicate a high level of incongruence between species and gene trees. The lack of resolution and congruence among trees can be explained by the sparse sampling (~ 0.45% of the currently accepted species) and by the low number of informative characters present in the sequences. Our study sheds light into the impact of data partitioning and methods over phylogenetic resolution and brings relevant information for the study of Mikania diversity and evolution, as well as for the Asteraceae family as a whole.

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The use of biotransformations in organic chemistry is widespread, with highlights of interesting applications in the functionalization of natural products containing unactivated carbons, like the kaurane diterpenes. A number of compounds with kaurane skeletons can be isolated in large amounts from several plant species and a myriad of biological activities has been related to these compounds. Studies on structure versus activity have showed that, in most cases, in kaurane diterpenes, activity increases with the increase of functionalization. Since naturally occurring kaurane diterpenes usually have limited functional groups to be used as targets for semi-synthetic modifications, production of more polar derivatives from kaurane diterpenes have been achieved mostly through the use of fungal biotransformations. In this review, selected examples the wonderful chemical diversity produced by fungi in kaurane diterpenes is presented. This diversity includes mainly hydroxylation of nearly all carbon atoms of the kaurane molecule, many of them carried out stereoselectively, as well as ring rearrangements, among other chemical modifications. Sources of starting materials, general biotransformation protocols employed, fungi with most consistent regioselectivity towards kaurane skeleton, as well as biological activities associated with starting materials and products are also described.

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Publisher Summary This chapter lists the important subjects on biological source that are discussed in the publication, such as Abies grandis Acanthodris nanaimoensis, Baccharis crispa, acanthosterol sulfates, Agelas dispar, Plasmodium falciparum, Podophyllum hexandrum, Quillaja saponaria, and Rauwolfia serpentina. The terms are mentioned along with the page numbers in which they are discussed in the publication.

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To date, Chagas disease has defied all attempts to develop an efficient and safe chemotherapy. Drugs effective on T. cruzi as trypanocidal agents may be classified as (a) drugs of extensive clinical use: Nifurtimox and Benznidazole; (b) drugs of restricted clinical use: azoles (e.g. Ketoconazole, Econazole; Miconazole); Amphotericin B; Allopurinol, Allopurinol ribosides and Primaquine; (d) drugs effective on T. cruzi and in experimental Chagas disease (murine model): alkyllysophospholipids; 5-amino-imidazole-4-carboxamides; bisbenzyl-isoquinolines; cruzipain (crucein) inhibitors; Gossipol; phenothiazines; d) drugs effective in vitro without other reported effects, acridines, actinomycin D, Crystal Violet (gentian violet), diterpenes (Mikania obtusata); N,N'-dimethyl-2-propen-1-amine, epoxidienthiol carbamates, Fe-chelators, guanyl hydrazones, o-naphthoquinones (beta-lapachone); quinoids (miconidine; tingenone); Olivacine, phenazine methosulfate, phenoxi-phenoxyl drugs, Proadifen, pyridinium azolate betaines, sesquiterpenes (Lychophora sp), sesquiterpene lactones, tetrahydrocarbazoles, DL-alpha-trifluoromethylarginine, triphenylmetane dyes. It is generally agreed that Nifurtimox and Benznidazole (a) are effective on acute Chagas' disease, but may not be effective in the chronic phase; (b) their effect depends on the susceptibility of T. cruzi strains to the drug; (c) they produce adverse effects in patients that may prevent prolonged treatments; they are genotoxic and produce biochemical damage in the mammalian tissues. Redox-cycling of Nifurtimox and Benznidazolee generates "reactive oxygen species" which explain the biological effects. At variance with the mammalian host, T. cruzi is deficient in antioxidant enzymes which are essential to prevent oxidative damage. Azoles are effective inhibitors of T. cruzi growth in vitro and in vivo since they inhibit sterol C14-delta 24(25) demethylase, an enzyme catalysing ergosterol production. Azoles reduce parasitemia and extend the survival of infected mice but do not produce parasitological cure and their clinical effectiveness is questionable. Allopurinol allopurinol ribosides and related compounds inhibit T. cruzi hypoxantine-guanine ribosyl transferase, thus preventing the synthesis of adenylic and guanylic acids and also DNA. They reduce parasitemia and negativize xenodiagnosis but these effects may not be permanent, which invalidates their clinical use. Cysteine-protease inhibitors recognize T. cruzi protease (cruzipain, crucein) active site, thus allowing a covalent linkage with the inhibitor. These peptide inhibitors are effective in acute and chronic murine models. Phenothiazines inhibit trypanothione reductase and a specially favoured fit is a small 2-substitued 2-chloro and 2-trifluoromethyl with a remote hydrophobic patch. The essential phenotiazine nucleus can adopt more than one inhibitory orientation in its binding site. Phenothiazines are promising trypanocidal agents for the treatment of Chagas' disease. The methodology for developing new drugs for the treatment of Chagas' disease is discussed.

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The diterpene ent-kaur-16-en-19-oic acid (1) was identified as the trypanocidal component of the ethanolic extract from Mikania obtusata D. C. (Asteraceae). This compound presents an IC50 of 0.5 mg/ml (1.66 mM) against the trypomastigote blood form of the Trypanosoma cruzi, the causative agent of Chagas' disease (American trypanosomiasis).

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