Umbrella Project III
Synthesis of Natural Products and their Synthetic Analogs
1. Study of bioactive butanolides’ synthesis through Morita-Baylis-Hillman reaction
Molecules containing the butanolide moiety are a class of compounds that have been extensively mentioned in the literature for its biological activities. These are composed of g-lactones originated from the 4-hidroxybutanoic acid and are frequently found in plants of the family Lauracea, including Lindera glauca, Lindera abtusilaba, Clinosteman mahuba, Actinodophe loncifalia, just to name a few. Several biological applications have been studied, such as antimicobacterial activity against M. tuberculosis H37Rv and cytotoxic activity against the cancer cell lines P388, A549 and Ht-29 and Hep2, showing its genotoxic activity. Since most of the mentioned butanolides are comprised of g-lactones ring containing long alkyl side chains α positioned to the ester carbonyl, a synthetic rout was devised to provide known compounds through total synthesis, using fast, efficient and green conditions, such as the Morita-Baylis-Hillman reaction.
In order to obtain the desired butanolides, we aim to use starting materials that are cheap and commercially accessible or industrial residues, more specifically; D-mannitol and glycerol. D-mannitol has the advantage of being a naturally occurring chiral compound, resulting in separable butanolide diastereomers, whilst glycerol is a renewable and versatile scaffold (Fig. 1).
Fig. 1. Retrosynthetic analysis of butanolides.
2. Synthesis and biological activities of cytosporones and analogs
Phenolic lipids constitute a class of bioactive compounds comprising molecules having hydrophobic tails linked to a phenolic polar head, widely distributed in nature, with great variety of biological and industrial potential. The cytosporones (Fig. 2), which are octaketide phenolic lipids, have been attracting the attention of many researchers owing to their biological potential, such as fungicidal, allelopathic, bactericidal and, cytotoxic activities. Recently, some new similar octaketides were isolated and a few synthetic approaches are reported in the literature. Many results point out that cytosporones are potential molecules to develop promising pharmaceutical and agrochemical agents.
As one more result of our phenolic lipids’ project, we performed the total synthesis of cytosporones A, B and C in just one synthetic route with excellent yields. Recently, also two new bioactive synthetic cytosporones, AMS049 (8) and AMS35AA (9), were synthesized by our research group from phthalide 10.
Fig. 2. Molecular structures of cytosporones A – E and synthetic analogs 6 – 10.
- de Araújo, F. GH. S.; de Figueiredo, D. R.; Auharek, S. A; Pesarini, J. R.; Meza, A.; Gomes, R. S.; Monreal, A. C. D.; Antoniolli-Silva, A. C. M. B.; de Lima, D. P.; Kassuya, C. A. L.; Beatriz, A.; Oliveira, R. J. In vivo Chemotherapeutic Insight of a Novel Isocoumarin (3-hexyl-5,7-dimethoxy-isochromen-1-one): Genotoxicity, cell death induction, leukometry and phagocytic evaluation. Genetics and Molecular Biology, 2017, 40, 665-675.
- Meza, A.; dos Santos, E. dos A.; Gomes, R. S. ; De Lima, D. P. ; Beatriz, A. Cytosporones: Isolation, Synthesis and Biological Activities of a Promising Class of Phenolic Lipids. Current Organic Synthesis, 2015, 12 (5): 618-638.
- Oliveira, R. J.; Navarro, S. D.; De Lima, D. P.; Meza, A.; Pesarini, J. R.; Gomes, R. S.; Karaziack, C. B.; Mauro, M. O.; Cunha-Laura, A. L.; Monreal, A. C. D.; Romão, W.; Lacerda Júnior, V.; Beatriz, A. A novel cytosporone 3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one: synthesis; toxicological, apoptotic and immunomodulatory properties; and potentiation of mutagenic damage. BMC Cancer, 2015, 561, 1-15.
- Navarro, S. D.; Beatriz, A.; Meza, A.; Pesarini, J. R.; Gomes, R. S.; Karaziack, C. B.; Laura, A. L. C.; Monreal, A. C. D.; Romão, W.; Lacerda Junior, V.; Mauro, M. O.; Oliveira, R. J. A new synthetic resorcinolic lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one: evaluation of toxicology and ability to potentiate the mutagenic and apoptotic effects of cyclophosphamide. European Journal of Medicinal Chemistry, p. 132-142, 2014.
- Zamberlam, C. E. M.; Meza, A.; Leite, C. B.; Marques, M. R.; de Lima, D. P.; Beatriz, A. Total synthesis and allelopathic activity of cytosporones A-C. Journal of the Brazilian Chemical Society, v. 23, p. 124-131, 2012.
- Beatriz, A.; de Lima, D. P.; Meza, A.; Karaziack, K. B.; Oliveira, R. J. Processo de Síntese de Nova Citosporona e Análogos e suas Aplicações como Adjuvantes na Terapia contra o Câncer, Potencializando os Efeitos da Ciclofosfamida. – Patent Nr. BR 102015010539-8 A2