Synthesis and Biological Evaluation of <i>N</i>-(Anthracen-9-ylmethyl)triamines as Molecular Recognition Elements for the Polyamine Transporter

Wang, Chaojie; Delcros, Jean‐Guy; Biggerstaff, John; Phanstiel, Otto

doi:10.1021/jm030028w

Cited by 98 publications

(236 citation statements)

References 41 publications

(117 reference statements)

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“…The ability of F14512 and etoposide to compete with [ 14 C]spermidine uptake was determined in L1210 cells in vitro according a procedure previously described (27). K i values for inhibition of spermidine uptake were determined using the Cheng Prussoff equation from the IC 50 values derived by iterative curve fitting of the sigmoidal equation describing the velocity of spermidine uptake of the respective competitor.…”

Section: Spermidine Uptake Inhibitionmentioning

confidence: 99%

“…CHO-MG cells, selected for its resistance to the antitumor agent methylglyoxalbis(guanylhydrazone), a cytotoxic analogue of spermidine which is substrate of the PTS, are deficient in polyamine uptake (26). These cells have been routinely used to define the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters (27,39). Comparison of drug cytotoxicity in these two cell lines provided an important screen to detect cell entry via the PTS.…”

Section: Pts-dependent Cytotoxicity Of F14512mentioning

confidence: 99%

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F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

Barret¹,

Kruczynski²,

Vispé³

et al. 2008

Cancer Research

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134

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The polyamine transport system (PTS) is an energy-dependent machinery frequently overactivated in cancer cells with a high demand for polyamines. We have exploited the PTS to selectively deliver a polyamine-containing drug to cancer cells. F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine tail supports three complementary functions: (a) facilitate formulation of a watersoluble compound, (b) increase DNA binding to reinforce topoisomerase II inhibition, and (c) facilitate selective uptake by tumor cells via the PTS. F14512 is 73-fold more cytotoxic to Chinese hamster ovary cells compared with CHO-MG cells with a reduced PTS activity. A decreased sensitivity of L1210 leukemia cells to F14512 was observed in the presence of putrescine, spermidine, and spermine. In parallel, the spermine moiety considerably enhances the drug-DNA interaction, leading to a reinforced inhibition of topoisomerase II. The spermine tail of F14512 serves as a cell delivery vehicle as well as a DNA anchor, and this property translates at the cellular level into a distinct pharmacologic profile. Twentynine human solid or hematologic cell lines were used to characterize the high cytotoxic potential of F14512 (median IC 50 of 0.18 Mmol/L). Finally, the potent antitumor activity of F14512 in vivo was evidenced with a MX1 human breast tumor xenograft model, with partial and complete tumor regressions. This work supports the clinical development of F14512 as a novel targeted cytotoxic drug and sheds light on the concept of selective delivery of drugs to tumor cells expressing the PTS. [Cancer Res 2008;68(23):9845-53]

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Section: Spermidine Uptake Inhibitionmentioning

confidence: 99%

Section: Pts-dependent Cytotoxicity Of F14512mentioning

confidence: 99%

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

Barret¹,

Kruczynski²,

Vispé³

et al. 2008

Cancer Research

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134

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“…Previous efforts revealed that the non-native triamine, homospermidine, showed a better PAT recognition than natural polyamines. A leading conjugate, anthracenylmethyl homospermidine (ANTMHspd), was found to display an excellent PAT selectivity and strong inhibitory effects on several tumor cell lines [6] . Many reports revealed that alkyl polyamine analogues exhibited cytotoxicity via apoptosis [7,8] , however, the antiproliferative mechanism of the homospermidine conjugates has not been elucidated until now.…”

Section: Introductionmentioning

confidence: 99%

A novel homospermidine conjugate inhibits growth and induces apoptosis in human hepatoma cells

Xie

Cheng

et al. 2007

Acta Pharmacol Sin

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Aim: To elucidate the mechanism responsible for the antiproliferative effects of a novel homospermidine conjugate, anthracenylmethyl homospermidine (ANTMHspd), in the human hepatoma BEL-7402 cell line. Methods: The viability of the cells was assessed by MTT assay and the trypan blue dye exclusion method. Morphological changes were observed by fluorescence microscopy with Hoechst 33258 staining. Cell cycle distribution, apoptosis, and mitochondrial membrane potential were measured by flow cytometry. Protein expression was detected by Western blot analysis. Results: ANTMHspd strongly decreased BEL-7402 cell proliferation in a dose-and time-dependent manner. Hoechst 33258 staining and the flow cytometry assay showed that ANTMHspd induced cell apoptosis and cell cycle perturbation. Furthermore, ANTMHspd could induce mitochondrial membrane potential loss and cytochrome c release and enhance cleaved caspase-3, cleaved caspase-9, and Bax protein expression without caspase-8 activation. ANTMHspd could also decrease the expression of Bcl-2 and cytochrome c in mitochondria. In addition, the specific inhibitors of caspase-9 and caspase-3 almost abolished the ANTMHspd-induced caspase-9 and caspase-3 activation, respectively. Conclusion: ANTMHspd could induce BEL-7402 cell apoptosis via the mitochondrial/caspase-dependent pathway and the Bcl-2 family was involved in the control of apoptosis.

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“…The anthracene-polyamine conjugates N1-anthracen-9-ylmethyl-butane-1,4-diamine [Ant-(butanediamine)]; N- (4-aminobutyl)-N-anthracen-9-ylmethylbutane-1,4-diamine [Ant- (4,4)]; N- [4-(4-aminobutylamino) butyl]-N-anthracen-9-ylmethylbutane-1,4-diamine [Ant- (4,4,4)]; N-(4-amino-butyl)-NЈ-(10-{[4-(4-amino-butylamino)butylamino]-methyl}anthracen-9-ylmethyl) butane-1,4-diamine (44-Ant-44); and benzene-polyamine conjugate N-(4-amino- were synthesized and characterized as previously described (21,(43)(44)(45). Their structures are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Polyamine Transport as a Target for Treatment ofPneumocystisPneumonia

Liao

Phanstiel

Lasbury

et al. 2009

Antimicrob Agents Chemother

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Polyamine levels are greatly increased in alveolar macrophages (AMs) during Pneumocystis pneumonia (PCP), leading to increased production of H 2 O 2 , which causes AMs to undergo apoptosis. One of the mechanisms by which polyamine levels in AMs are elevated is enhanced uptake of exogenous polyamines. In this study, the possibility of targeting polyamine uptake as a treatment for PCP was examined. Pneumocystis pneumonia (PCP) is the leading opportunistic disease in AIDS patients. PCP can be life threatening, as it may cause extensive pulmonary injury, impaired gas exchange, and respiratory failure. The first-line drug for both prophylaxis and treatment of PCP is a combination of trimethoprim and sulfamethoxazole (TMP-SMZ) (40). TMP and SMZ inhibit dihydrofolate reductase and dihydropteroate synthase (DHPS), respectively (18). However, TMP-SMZ may cause adverse effects, such as fever and rash (37), and TMP-SMZ-resistant Pneumocystis strains have emerged (28), probably due to point mutations at codon 55 or 57 of the DHPS gene of Pneumocystis jirovecii (18,41). Clindamycin-primaquine, atovaquone, and pentamidine are alternative therapies for PCP; however, they are also associated with the issues of side effects.Another potential target for treatment of PCP is polyamine synthesis (8,9,14,32,36,39). Polyamines are essential organic compounds for cell growth (20,26). The rate-limiting enzyme of polyamine synthesis is ornithine decarboxylase (ODC), which is usually increased in proliferating cells. ␣-Difluoromethylornithine (DFMO, also known as eflornithine) is a potent ODC inhibitor with low cytotoxicity. DFMO was first developed as an anticancer drug and was shown to be effective for treatment of trypanosomiasis (2,29). It also has activity against Plasmodium falciparum (30), Giardia lamblia (13), Eimeria tenella (16), and Trichomonas vaginalis (47). DFMO has also been used to treat PCP in humans, with success rates ranging from 33 to 57% (14,32,36,38,39). This partial success suggests that targeting polyamine synthesis alone is not sufficient for treatment of PCP.Our recent studies revealed that polyamine levels in alveolar macrophages (AMs) are greatly increased during PCP, resulting in an elevated apoptosis rate and impaired Pneumocystis clearance activity by AMs (23). We also found that the increased intracellular polyamine levels were at least partially due to increased uptake of exogenous polyamines (25). Based on these findings, we hypothesized that polyamine uptake can be a target for treatment of PCP and tested five potential polyamine transport (PAT) inhibitors. Results showed that compound 44-Ant-44 was effective against PCP in a rat model.

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Synthesis and Biological Evaluation of N-(Anthracen-9-ylmethyl)triamines as Molecular Recognition Elements for the Polyamine Transporter

Cited by 98 publications

References 41 publications

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

A novel homospermidine conjugate inhibits growth and induces apoptosis in human hepatoma cells

Polyamine Transport as a Target for Treatment ofPneumocystisPneumonia

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