Dionissios Papaioannou

Structure, Biological Activity and Synthesis of Polyamine Analogues and Conjugates

The structure and the biological significance of naturally occurring and synthetic polyamine analogues and conjugates are presented and the available methodologies for their synthesis are described. These methodologies involve either the selective functionalization of the amino functions, using suitable protecting groups or acylating agents, or fragment synthesis protocols. The latter employ suitable amino components and simple reactions, like Michael addition to α,β-unsaturated nitriles, alkylation of amines and sulfonamides, reductive alkylation and acylation followed by reduction of the thus-obtained amides, as key-reactions, or azides as key-intermediates, for the assembly of the polyamine skeleton. Syntheses performed in solution as well as in the solid phase are discussed.

Kukoamine A analogs with lipoxygenase inhibitory activity

Kukoamine A (KukA) is a spermine (SPM) conjugate with dihydrocaffeic acid (DHCA), with interesting biological activities. The four possible regioisomers of KukA, as well as a series of KukA analogs incorporating changes in either the SPM or the DHCA structural units, were evaluated for their antioxidant activity and their inhibitory activity on soybean lipoxygenase (LOX) and lipid peroxidation. The reducing properties of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay and found to be in the range 5–97.5%. KukA significantly inhibits LOX with IC50 9.5 μM. All tested analogs inhibited lipid peroxidation in the range of 11–100%. The most potent compounds KukA and its analog 3, in which the DHCA units had been replaced by O,O9-dimethylcaffeic acid units, were studied for their anti-inflammatory activity in vivo on rat paw edema induced by carrageenan and found to be of comparable activity to indomethacin. The results of the biological tests are discussed in terms of structural characteristics.

Syntheses and evaluation of the antioxidant activity of acitretin analogs with amide bond(s) in the polyene spacer.

Ester analogs of the antipsoriatic drug acitretin were synthesized by coupling either anilines with N-protected indole-3-carboxylic acid, followed by deprotection and coupling with O-monoprotected dicarboxylic acids or Wittig reaction of indole-3-carboxaldehyde, 3-acetyl-1-tosylpyrrole and 4-amino-9-fluorenone with Ph3P=CHCO2tBu, followed by N-deprotection, where necessary, and finally coupling with cinnamoyl fluorides. Corresponding free acids were obtained through TFA-mediated carboxyl group deprotection. Although these analogs and acitretin showed very low reducing abilities, analogs 5, 6, 8 and 12 strongly inhibited LOX with IC50 values ranging from 35-65 microM. Acitretin and its analogs 5-7, 10, 11 and 15 inhibited lipid peroxidation more strongly than trolox whereas acitretin and analog 4 were in vivo more potent anti-inflammatory agents on rat paw oedema induced by Carrageenan than indomethacin.

Simple fragment syntheses of all four isomers of the spermine alkaloid kukoamine

Abstract All four isomers of the spermine alkaloid kukoamine were unambiguously prepared through diacylation with O,O′ -dibenzylcaffeyl chloride of suitably protected (benzyl and/or trityl groups) spermine derivatives, assembled on solid and/or in liquid phase using β-alanine and γ-aminobutyric acid, followed by simultaneous N- and O- deprotection and double bond reduction using catalytic hydrogenation.

Conjugation with polyamines enhances the antibacterial and anticancer activity of chloramphenicol

Chloramphenicol (CAM) is a broad-spectrum antibiotic, limited to occasional only use in developed countries because of its potential toxicity. To explore the influence of polyamines on the uptake and activity of CAM into cells, a series of polyamine–CAM conjugates were synthesized. Both polyamine architecture and the position of CAM-scaffold substitution were crucial in augmenting the antibacterial and anticancer potency of the synthesized conjugates. Compounds 4 and 5, prepared by replacement of dichloro-acetyl group of CAM with succinic acid attached to N4 and N1 positions of N8,N8-dibenzylspermidine, respectively, exhibited higher activity than CAM in inhibiting the puromycin reaction in a bacterial cell-free system. Kinetic and footprinting analysis revealed that whereas the CAM-scaffold preserved its role in competing with the binding of aminoacyl-tRNA 3′-terminus to ribosomal A-site, the polyamine-tail could interfere with the rotatory motion of aminoacyl-tRNA 3′-terminus toward the P-site. Compared to CAM, compounds 4 and 5 exhibited comparable or improved antibacterial activity, particularly against CAM-resistant strains. Compound 4 also possessed enhanced toxicity against human cancer cells, and lower toxicity against healthy human cells. Thus, the designed conjugates proved to be suitable tools in investigating the ribosomal catalytic center plasticity and some of them exhibited greater efficacy than CAM itself.

Simple total syntheses of N-substituted polyamine derivatives using N-tritylamino acids

Abstract A general methodology for the total synthesis of N -alkyl- and acylpolyamine derivatives is described which is based on the coupling of suitable N -tritylamino acids with amines followed by lithium aluminium hydride reduction of the thus obtained amides.

Simple syntheses of N-alkylated spermidine fragments and analogues of the spermine alkaloid kukoamine A

Abstract Acylation of a variety of amines with succinimidyl N -trityl-β-alanyl-γ-aminobutyrate and N -trityl-γ-aminobutyryl-β-alaninate, readily obtained through coupling of succinimidyl N -trityl-β-alaninate with trimethylsilyl γ-aminobutyrate and of N -trityl-γ-aminobutyric acid with methyl β-alaninate, respectively, followed by LiAlH 4 reduction, produced N -monoalkylated spermidine fragments and analogues of the spermine alkaloid kukoamine A. The applicability of this methodology on the solid phase was also demonstrated.

Simple syntheses of cyclic polyamines using selectively N-tritylated polyamines and succinic anhydride

Abstract Treatment of selectively N -tritylated spermidine and spermine derivatives with succinic anhydride, followed by PyBrOP-mediated intramolecular amide bond formation and LiAlH 4 reduction, allows for an easy and general entry to cyclic polyamine derivatives.

Effect of an all-trans-retinoic acid conjugate with spermine on viability of human prostate cancer and endothelial cells in vitro and angiogenesis in vivo

Retinoids constitute a family of organic compounds that are being used for the treatment of various diseases, ranging from acne vulgaris to acute promyelocytic leukemia. Their use however is limited due to serious adverse effects and there is a great need for analogues with better safety profile. In the present work, the effect of N(1),N(12)-bis(all-trans-retinoyl)spermine (RASP), a conjugate of all-trans-retinoic acid (atRA) with spermine, on angiogenesis in vivo and viability of human endothelial and prostate cancer cells in vitro were studied. Both atRA and RASP dose-dependently inhibited angiogenesis in the chicken embryo chorioallantoic membrane model. RASP was more effective and could be used in a wider dose range due to lower toxicity compared with atRA. Both retinoids decreased the number of human umbilical vein endothelial and prostate cancer LNCaP and PC3 cells in a concentration-dependent manner. RASP was more effective and potent compared with atRA, spermine, their combination, or conjugates of spermine with other acidic retinoids and/or psoralens in prostate cancer cells. The inhibitory effect of both atRA and RASP seems to be related to an increase of the tumour repressing gene retinoic acid receptor beta mRNA, was mediated by retinoic acid receptor alpha, and was proportional to endogenous retinoic acid receptor beta expression. These data suggest that RASP is more effective than atRA in decreasing angiogenesis and prostate cancer cell growth and identify retinoic acid receptor alpha as the receptor through which it causes retinoic acid receptor beta up-regulation and decrease of prostate cancer cell growth.

Model studies towards the applicability of the readily available (S)-N-tritylaspartic anhydride in the synthesis of amino acids and peptides

Abstract Reactions of N-tritylaspartic acid anhydride, readily available through N,N′-dicyclohexylcarbodiimide-mediated dehydration of N-tritylaspartic acid, with Grignard and Wittig reagents, bulky hydrides, and amines or alcohols of the benzhydryl type, lead regioselectively to products from attack at the β-carbonyl function.