The use of Fukuyama's sulfonamide in the synthesis of selectively protected spermidines

Abstract

A diferenciação dos grupos amino terminais de poliaminas freqüentemente envolve uma série de etapas de proteção e desproteção, resultando em rotas sintéticas longas e de baixo rendimento global. Tendo em vista o relevante papel biológico atribuído a estas substâncias, torna-se necessário o desenvolvimento de sínteses mais eficientes para poliaminas. Neste artigo descrevemos uma síntese de duas espermidinas seletivamente protegidas, empregando a sulfonamida de Fukuyama. As duas sínteses foram executadas em três etapas a partir da 1,3-propanodiamina, com um rendimento global superior a 40%.The differentiation of terminal amino groups in polyamines usually involves a series of protection and deprotection steps, leading to long reaction sequences with low overall yields. Given the relevance of the biological activities displayed by polyamines, the development of more efficent synthetic routes for these compounds is highly desired. Herein we report the synthesis of two selectively protected spermidines, using Fukuyama's sulfonamide. Both syntheses were performed in three steps, starting from 1,3-diaminopropane, with an overall yield higher than 40%. Keywords: polyamines, spermidine, Fukuyama's sulfonamide IntroductionIn the past decades a great deal of attention has been given to polyamines, especially because of their involvement in the regulation of cellular functions, such as cell proliferation and differentiation.1 Additionally, a wide range of biological activities have been attributed to polyamines conjugates and derivatives, such as antianigogenic, anticancer, and neurotoxins, to name a few. 2The metabolism of polyamines in prokaryotes has also gained increased importance.3 In fact, the inhibition of enzymes involved in the metabolism of parasitic protozoa has been recognized as a promising strategy for the chemotherapy of tropical diseases. 4 For instance, the inhibition of ornithine descaboxylase by a-difluoromethylornithine, a drug candidate against African sleeping sickness and malaria, 4,5 blocks the first step of polyamine biosynthetic pathway.6 Trypanothione, structurally characterized as N 1 ,N 8 -bis(glutathionyl)spermidine, is a polyamine derivative used by trypanosomatids as a defense against reactive oxygen species during their infective cycle. 7 The metabolism of trypanothione is another target for drug development against trypanosomiases and leishmanioses. 8As part of a research program aiming the synthesis of peptide-polyamine conjugates, we became interested in the preparation of selectively protected spermidines. 9 However, the synthesis of unsymmetrical polyamines usually requires several protection and deprotection steps, making such approaches unnatractive due to the long reaction sequences involved. 10 More straighforward alternatives to acess polyamine backbones are needed.The dual role of Fukuyama's sulfonamide, 11 which not only masks the amino group, but also activates it to grow the polyamine chain, meet the requirements to solve those issues.12 Herein, we wish to describe a versatile...

Antitumoral activity of new polyamine-naphthoquinone conjugates

“…Polyamine-1,4-naphthoquinone conjugates 5a-c (14) were synthesized as follows: i) methylation of lapachol 2b and nor-lapachol 2c with dimethylsulphate in acetone and potassium carbonate, to yield 3b (77%) (15) and 3c (71%) (16), respectively, and synthesis of methoxylawsone (3a) from the sodium salt of 1,2-naphthoquinone-4-sulfonic acid (17); ii) preparation of the protected derivative of spermidine 4 in a four-step synthesis (18,19); iii) nucleophilic displacement of the methoxyquinones 3a-c with compound 4. To the solution 4 (110.0 mg; 0.40 mmol) in MeOH (2 ml) in a sealed tube, was added a solution of 3b (100.0 mg; 0.30 mmol) in MeOH (5 ml).…”

Versatile Procedure for Asymmetric and Orthogonal Protection of Symmetric Polyamines and Its Advantages for Solid Phase Synthesis

“…This method is especially favorable for commercially available backbones such as spermine. However, this requires an efficient protection of the primary and secondary amino groups in a solution phase synthesis step. ,– For high throughput library productions and large-scale SPS, large quantities of highly stable and partially or fully protected polyamine building blocks are required. They should be asymmetrically protected to exclude cross-linking reactions that would severely decrease yields and purities of the solid phase synthesis.…”