Synthesis of Polyamines, Their Derivatives, Analogues and Conjugates

Kuksa, Vladimir; Buchan, Robert; Lin, Paul Kong Thoo

doi:10.1055/s-2000-6405

Cited by 110 publications

(92 citation statements)

References 54 publications

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Section: Introductionmentioning

confidence: 99%

“…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 route for two orthogonally protected spermidines using Fukuyama's sulfonamide. …”

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

Silva

Fona

Lima

2004

J. Braz. Chem. Soc.

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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...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Silva

Fona

Lima

2004

J. Braz. Chem. Soc.

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“…[1][2][3][4] They interact with nucleic acids and modulate DNA synthesis and cell proliferation. [5][6][7] Due to their biological significance, practical and versatile synthetic methods are needed, but the lability of these compounds to oxidation, as well as their highly polar nature, makes handling difficult.…”

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confidence: 99%

Practical Synthesis of Spermine, Thermospermine and Norspermine

Kariya

Asanuma

Inai

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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Polyamines, such as spermine (1), thermospermine (2) and norspermine (3), are widely distributed in nature, and have multiple biological activities. In addition, many of their conjugates have potential for pharmacological use. Here, we present a solid-phase synthesis using our nitrobenzenesulfonyl (Ns) strategy, which can provide 1, 2 and 3 on a gram scale. This approach should be suitable for facile construction of a diverse library of polyamines.

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“…This may be due, in part, to the difficulties in obtaining pure samples of these compounds from the natural sources † as well as to the fact that most syntheses described thus far provided only racemic material. Prototype spermidine alkaloids are (Ϫ)-isooncinotine (1), (Ϫ)-oncinotine (2), (Ϫ)-neooncinotine (3), and oncinodin-12-one (4), which were isolated from the stem bark of Oncinotis nitida and Oncinotis tenuiloba (Apocynaceae) (5)(6)(7) and have been repeatedly targeted in the past (8)(9)(10)(11)(12) (Fig. 1).…”

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Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine

Scheiper

Glorius

Leitner

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

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A concise and efficient total synthesis of the spermidine alkaloid (؊)-isooncinotine (1) incorporating a 22-membered lactam ring is outlined. The approach is largely catalysis-based, involving a selective iron-catalyzed alkyl-aryl cross-coupling reaction of a difunctionalized pyridine substrate, a heterogeneous asymmetric hydrogenation step to set the chiral center of the target, and a highly integrated ring-closing metathesis͞hydrogenation sequence to forge the saturated macrocyclic edifice in a single operation. Despite the prevalence of the biogenetic bases spermidine and spermine in nature and their widespread use as tools in biochemical research (1), little is known about the physiological properties of the small but structurally rather unique class of alkaloids incorporating these polyamines into their macrocyclic skeletons (2-4). This may be due, in part, to the difficulties in obtaining pure samples of these compounds from the natural sources † as well as to the fact that most syntheses described thus far provided only racemic material. Prototype spermidine alkaloids are (Ϫ)-isooncinotine (1), (Ϫ)-oncinotine (2), (Ϫ)-neooncinotine (3), and oncinodin-12-one (4), which were isolated from the stem bark of Oncinotis nitida and Oncinotis tenuiloba (Apocynaceae) (5-7) and have been repeatedly targeted in the past (8-12) (Fig. 1). Only recently has one member of this series (i.e., compound 2) been made available in an optically active form through total synthesis by using a diastereoselective 1,3-dipolar cycloaddition for the formation of the stereogenic center at the junction of the piperidine and the macrocyclic ring (13).In pursuit of previous work in the field of polyamine alkaloids (14, 15), we were prompted to develop a complementary, practical, and potentially scaleable entry into this family of natural products, choosing the 22-membered macrolactam (Ϫ)-isooncinotine 1 as our initial target. The envisaged route, however, should not only provide material for further evaluation but also meet a set of stringent chemical criteria. Specifically, it is felt that contemporary organic chemistry must (i) prioritize catalysis-based bond formations, (ii) try to control absolute stereochemistry by asymmetric catalysis, and (iii) aim at high convergence combined with an overall ''economy of steps'' (16). Furthermore, the total synthesis of 1 should provide us with the possibility to scrutinize methodology developed in our laboratories. Outlined below is the successful reduction of this plan to practice. Materials and MethodsGeneral. All reactions were carried out under Ar in flame-dried glassware. The solvents used were purified by distillation over the drying agents indicated and were transferred under Ar: tetrahydrofuran (THF) (Na), CH 2 Cl 2 (P 4 O 10 ), MeCN, Et 3 N, pyridine, NMP, hexamethylphosphoramide (HMPA), tetramethylethylenediamine (CaH 2 ), dimethylformamide (DMF) (dibutyltin dilaurate͞Desmodur), MeOH, EtOH (Mg), and toluene (Na͞K). For flash chromatography, Merck silica gel 60 (230-400 mesh) was used. F...

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Synthesis of Polyamines, Their Derivatives, Analogues and Conjugates

Cited by 110 publications

References 54 publications

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

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

Practical Synthesis of Spermine, Thermospermine and Norspermine

Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine

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