Polyamine-based analogs and conjugates as antikinetoplastid agents

Jagu, Elodie; Pomel, Sébastien; Pèthe, Stéphanie; Loiseau, Philippe M.; Labruère, Raphaël

doi:10.1016/j.ejmech.2017.08.014

Cited by 18 publications

(17 citation statements)

References 148 publications

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“…There are many literature reports of monosubstituted diamines, but surprisingly, no precedents of bioactive tetrasubstituted aliphatic diamine analogs as antiparasitic agents [24]. With that idea in mind, ten tetrasubstituted analogs were prepared.…”

Section: Resultsmentioning

confidence: 99%

A minimalistic approach to develop new anti-apicomplexa polyamines analogs

Panozzo-Zénere

Porta

Arrizabalaga

et al. 2018

European Journal of Medicinal Chemistry

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The development of new chemical entities against the major diseases caused by parasites is highly desired. A library of thirty diamines analogs following a minimalist approach and supported by chemoinformatics tools have been prepared and evaluated against apicomplexan parasites. Different member of the series of N,N′−disubstituted aliphatic diamines shown in vitro activities at submicromolar concentrations and high levels of selectivity against Toxoplasma gondii and in chloroquine-sensitive and resistant-strains of Plasmodium falciparum. In order to demonstrate the importance of the secondary amines, ten N,N,N′,N′−tetrasubstituted aliphatic diamines derivatives were synthesized being considerably less active than their disubstituted counterpart. Theoretical studies were performed to establish the electronic factors that govern the activity of the compounds.

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Section: Resultsmentioning

confidence: 99%

A minimalistic approach to develop new anti-apicomplexa polyamines analogs

Panozzo-Zénere

Porta

Arrizabalaga

et al. 2018

European Journal of Medicinal Chemistry

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“…A second generation of polyamine analogues are unsymmetrically substituted compounds that display structure-dependent and cell type specific effects on polyamine metabolism [ 17 , 79 , 80 ]. Another series of polyamine analogues are designated as conformationally restricted, cyclic oligoamines [ 81 ].…”

Section: Polyamine Analogues and Breast Cancer Therapeuticsmentioning

confidence: 99%

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

Thomas

2018

Medical Sciences

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Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine N1-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents.

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“…2,3,[12][13][14][15][16][17][18][19] We were recently interested in the selective mono-functionalization of the unsymmetrical Tsm and we therefore decided to attempt the synthesis of orthogonally protected Tsm using the fragment synthesis protocol. It should be noted that mono-functionalization of the symmetrical PA Spm has been effected by using the N 1 ,N 4 ,N 8 -Boc3-Spm obtained via the low temperature selective mono-trifluoroacetylation of Spm. 20 Tsm has been first prepared by Ganem et al from Spd through a five-steps sequence.…”

Section: Introductionmentioning

confidence: 99%

“…Nosyl-N4 -tritylputrescine(14).Reaction time: 2 h; slightly yellow solid; (1.59 g, 88%); mp 149-152 o C; Rf (N): 0.36; 1 H NMR (600 MHz, CDCl3) δ 8.14-8.10 (m, 1H), 7.87-7.83 (m, 1H), 7.74-7.70 (m, 2H), 7.44-7.41 (m, 6H), 7.28-7.24 (m, 6H), 7.20-7.16 (m, 3H), 5.29 (t, J = 6.6 Hz, 1H), 3.08 (q, J = 6.6 Hz, 2H), 2.11 (t, J = 6.6 Hz, 2H) 1.61 (quint., J = 6.6 Hz, 2H), 1.55 (br. s, 1H), 1.48 (quint., J = 6.6 Hz, 2H)…”

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confidence: 99%

General Approach for the Liquid-Phase Fragment Synthesis of Orthogonally Protected Naturally Occurring Polyamines and Applications Thereof

et al. 2019

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Orthogonally protected polyamines (PAs) have been synthesized using α,ωdiamines and ω-aminoalcohols as N-Cx-N and N-Cy synthons, respectively, and the Mitsunobou reaction as the key reaction for the assembly of the PA skeleta. The Trt, Dde and Phth groups have been employed for protecting the primary amino functions and the Ns group for activating the primary amino functions towards alkyla-2 tion and secondary amino function protection. The approach has been readily extended to accommodate the total synthesis of the spider toxins Agel 416 and HO-416b incorporating the 3-4-3-3 and the 3-3-3-4 PA skeleton, respectively.

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Polyamine-based analogs and conjugates as antikinetoplastid agents

Cited by 18 publications

References 148 publications

A minimalistic approach to develop new anti-apicomplexa polyamines analogs

A minimalistic approach to develop new anti-apicomplexa polyamines analogs

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

General Approach for the Liquid-Phase Fragment Synthesis of Orthogonally Protected Naturally Occurring Polyamines and Applications Thereof

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