Effect of Polyamine Homologation on the Transport and Biological Properties of Heterocyclic Amidines

Abstract

Five sets of heterocyclic derivatives of various sizes and complexities coupled by an amidine function to putrescine, spermidine, or spermine were prepared. They were essentially tested to determine the influence of the polyamine chain on their cellular transport. To comment on affinity and on selective transport via the polyamine transport system (PTS), K(i) values for polyamine uptake were determined in L1210 cells, and the cytotoxicity and accumulation of the conjugates were determined in CHO and polyamine transport-deficient mutant CHO-MG cells, as well as in L1210 and alpha-difluoromethylornithine- (DFMO-) treated L1210 cells. Unlike spermine, putrescine and spermidine were clearly identified as selective motifs that enable cellular entry via the PTS. However, this property was clearly limited by the size of substituents: these polyamines were able to ferry a dihydroquinoline system via the PTS but did not impart any selectivity to bulkier substituents.

RETRACTED ARTICLE: NPC-16, a novel naphthalimide–polyamine conjugate, induced apoptosis and autophagy in human hepatoma HepG2 cells and Bel-7402 cells

“…Therefore, the elevated requirement of tumor cells for polyamines makes the polyamine pathway attractive for tumor targeted chemotherapy [2,3]. Recent data revealed that polyamines are potential vehicles to carry diverse cytotoxic drugs [4,5], this idea was on account of tumor cells could import both native and structurally modified polyamines from exogenous sources via the active polyamine transporter (PAT) which is up-regulated in many tumor cell lines [4,5].…”

N-ω-chloroacetyl-l-ornithine, a new competitive inhibitor of ornithine decarboxylase, induces selective growth inhibition and cytotoxicity on human cancer cells versus normal cells

“…The active and passive transport systems of tumor cells have a greater capacity than those of normal cells. Tumor cells need this greater capacity to constantly supply the large quantity of nutrients needed to support their characteristic unabated growth [62][63][64] . Whereas the lack of effectivenes of DFMO as a chemotherapeutic agent seems to be due to its poor transport into the cells 11 , NCAO apparently utilizes the efficient transport capacity of tumor cells.…”

Current Developments in Using MESO-(TETRA) Substituted Porphyrins for PDT

“…Previous studies have shown that the PTS can readily take up heterocyclic derivatives if conjugated to natural polyamines. 38 Hence, recent studies in PDT have focused on comparing the efficacy of porphyin-polyamine conjugates in relation to Photofrin. These studies indicate a better efficiency of polyamine conjugates over the clinically approved PS.…”

“…41,42 The results suggest that carboranylchlorins are good candidates for this dual treatment modality and warrant further investigations. Recently, seven polyamine conjugates of a tri(p-carboranylmethylthio)-tetrafluorophenylporphyrin (33)(34)(35)(36)(37)(38)(39) were prepared in high yields by sequential substitution of the p-phenyl fluoride of tetrakis(pentafluorophenyl)porphyrin (TPPF) (Fig. 9).…”