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1.
Int J Mol Sci ; 24(19)2023 Sep 26.
Article in English | MEDLINE | ID: mdl-37834037

ABSTRACT

Topoisomerases are interesting targets in cancer chemotherapy. Here, we describe the design and synthesis of a novel copper(II) indenoisoquinoline complex, WN198. The new organometallic compound exhibits a cytotoxic effect on five adenocarcinoma cell lines (MCF-7, MDA-MB-231, HeLa, HT-29, and DU-145) with the lowest IC50 (0.37 ± 0.04 µM) for the triple-negative MDA-MB-231 breast cancer cell line. Below 5 µM, WN198 was ineffective on non-tumorigenic epithelial breast MCF-10A cells and Xenopus oocyte G2/M transition or embryonic development. Moreover, cancer cell lines showed autophagy markers including Beclin-1 accumulation and LC3-II formation. The DNA interaction of this new compound was evaluated and the dose-dependent topoisomerase I activity starting at 1 µM was confirmed using in vitro tests and has intercalation properties into DNA shown by melting curves and fluorescence measurements. Molecular modeling showed that the main interaction occurs with the aromatic ring but copper stabilizes the molecule before binding and so can putatively increase the potency as well. In this way, copper-derived indenoisoquinoline topoisomerase I inhibitor WN198 is a promising antitumorigenic agent for the development of future DNA-damaging treatments.


Subject(s)
Antineoplastic Agents , Topoisomerase I Inhibitors , Humans , Topoisomerase I Inhibitors/pharmacology , Copper/pharmacology , Cell Proliferation , Topoisomerase Inhibitors/pharmacology , Antineoplastic Agents/chemistry , DNA/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Molecular Structure , Structure-Activity Relationship , Apoptosis
2.
Front Oncol ; 12: 837373, 2022.
Article in English | MEDLINE | ID: mdl-35280788

ABSTRACT

Topoisomerases, targets of inhibitors used in chemotherapy, induce DNA breaks accumulation leading to cancer cell death. A newly synthesized copper(II) indenoisoquinoline complex WN197 exhibits a cytotoxic effect below 0.5 µM, on MDA-MB-231, HeLa, and HT-29 cells. At low doses, WN197 inhibits topoisomerase I. At higher doses, it inhibits topoisomerase IIα and IIß, and displays DNA intercalation properties. DNA damage is detected by the presence of γH2AX. The activation of the DNA Damage Response (DDR) occurs through the phosphorylation of ATM/ATR, Chk1/2 kinases, and the increase of p21, a p53 target. WN197 induces a G2 phase arrest characterized by the unphosphorylated form of histone H3, the accumulation of phosphorylated Cdk1, and an association of Cdc25C with 14.3.3. Cancer cells die by autophagy with Beclin-1 accumulation, LC3-II formation, p62 degradation, and RAPTOR phosphorylation in the mTOR complex. Finally, WN197 by inhibiting topoisomerase I at low concentration with high efficiency is a promising agent for the development of future DNA damaging chemotherapies.

3.
Cancers (Basel) ; 12(10)2020 Oct 05.
Article in English | MEDLINE | ID: mdl-33027952

ABSTRACT

Organometallics, such as copper compounds, are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topology. Copper complexes inhibitors of topoisomerases 1 and 2 work by different molecular mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS production, and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clinical trials and future cancer therapy.

4.
Org Lett ; 22(13): 5157-5162, 2020 Jul 02.
Article in English | MEDLINE | ID: mdl-32575988

ABSTRACT

Piperazines are privileged scaffolds in medicinal chemistry. Disclosed herein is a visible-light-promoted decarboxylative annulation protocol between a glycine-based diamine and various aldehydes to access 2-aryl, 2-heteroaryl, as well as 2-alkyl piperazines. The iridium-based complex [Ir(ppy)2(dtbpy)]PF6 and carbazolyl dicyanobenzene 4CzIPN were found to be the photocatalysts of choice to efficiently perform the transformation under mild conditions, whether in batch or in continuous mode.

5.
Int J Mol Sci ; 21(9)2020 Apr 26.
Article in English | MEDLINE | ID: mdl-32357477

ABSTRACT

Xenopus oocytes were used as cellular and molecular sentinels to assess the effects of a new class of organometallic compounds called ferrocenyl dihydroquinolines that have been developed as potential anti-cancer agents. One ferrocenyl dihydroquinoline compound exerted deleterious effects on oocyte survival after 48 h of incubation at 100 µM. Two ferrocenyl dihydroquinoline compounds had an inhibitory effect on the resumption of progesterone induced oocyte meiosis, compared to controls without ferrocenyl groups. In these inhibited oocytes, no MPF (Cdk1/cyclin B) activity was detected by western blot analysis as shown by the lack of phosphorylation of histone H3. The dephosphorylation of the inhibitory Y15 residue of Cdk1 occurred but cyclin B was degraded. Moreover, two apoptotic death markers, the active caspase 3 and the phosphorylated histone H2, were detected. Only 7-chloro-1-ferrocenylmethyl-4-(phenylylimino)-1,4-dihydroquinoline (8) did not show any toxicity and allowed the assembly of a histologically normal metaphase II meiotic spindle while inhibiting the proliferation of cancer cell lines with a low IC50, suggesting that this compound appears suitable as an antimitotic agent.


Subject(s)
Ferrous Compounds/pharmacology , Oocytes/physiology , Progesterone/pharmacology , Quinolines/pharmacology , Xenopus Proteins/metabolism , Animals , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin B/metabolism , Female , Ferrous Compounds/chemistry , Gene Expression Regulation/drug effects , HeLa Cells , Histones/metabolism , Humans , Meiotic Prophase I , Molecular Structure , Oocytes/drug effects , Phosphorylation , Quinolines/chemistry , Xenopus laevis/metabolism
6.
ChemSusChem ; 12(14): 3370-3376, 2019 Jul 19.
Article in English | MEDLINE | ID: mdl-31013551

ABSTRACT

Environmental regulation and depletion of fossil resources are boosting the search for new polymeric materials produced from biomass. Here, the synthesis of a new diester bearing a pendant lactam unit from methyl levulinate and aspartic acid is reported. The palladium-catalyzed reductive amination/cyclization sequence was carefully optimized to afford the diacid with high yield (>95 %). In a second step, the compound was esterified to give the corresponding diester. The latter monomer was copolymerized with α-ω linear diols, yielding polyesters with molecular weights up to 20.5 kg mol-1 .

7.
Bioorg Med Chem ; 24(4): 651-60, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26740155

ABSTRACT

Three series of indeno[1,2-c]isoquinolines bearing a ferrocenyl entity were synthesized and evaluated for DNA interaction, topoisomerase I and II inhibition, and cytotoxicity against breast human cancer cell lines. In the first and second series, the ferrocenyl scaffold was inserted as a linker between the two nitrogen atoms. In the last series, it was introduced at the end of the carbon chain. The present study showed that the ferrocenyl entity enhanced the topoisomerase II inhibition. Most compounds showed a potent growth inhibitory effect on MDA-MB-231 cell line with the IC50 in µM range.


Subject(s)
Antineoplastic Agents/pharmacology , DNA-Binding Proteins/antagonists & inhibitors , Ferrous Compounds/chemical synthesis , Ferrous Compounds/pharmacology , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Antigens, Neoplasm/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Ferrous Compounds/chemistry , Humans , Inhibitory Concentration 50 , Isoquinolines/chemistry , Molecular Structure , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemistry , Tumor Cells, Cultured
8.
Eur J Med Chem ; 90: 519-25, 2015 Jan 27.
Article in English | MEDLINE | ID: mdl-25486423

ABSTRACT

The aim of this study was to synthesize a series of ferrocenyl 4-aminoquinolines and to evaluate their activities against Plasmodium falciparum F32 (chloroquine-sensitive) and FCB1 and K1 (chloroquino-resistant). Some of the ferrocenyl compounds exhibited in vitro antiplasmodial activity in the nM range. In particular, (1R,4R)-N1-(7-chloroquinolin-4-yl)-N4-(ferrocenylmethyl)-N4-methylcyclohexane-1,4-diamine 17 presented the lowest IC50 value (26 nM) against CQ-resistant strains.


Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Ferrous Compounds/chemical synthesis , Ferrous Compounds/pharmacology , Plasmodium falciparum/drug effects , Quinolines/chemical synthesis , Quinolines/pharmacology , Antimalarials/chemistry , Dose-Response Relationship, Drug , Ferrous Compounds/chemistry , Molecular Structure , Parasitic Sensitivity Tests , Quinolines/chemistry , Structure-Activity Relationship
9.
Org Lett ; 16(11): 2982-5, 2014 Jun 06.
Article in English | MEDLINE | ID: mdl-24851939

ABSTRACT

The first enantioselective synthesis of 4-aza-podophyllotoxin derivatives by partial transfer hydrogenation of lactone-fused quinolines was achieved using a chiral Brønsted acid catalyst. This reaction was extended to a large scope of substrates with good yields and enantioselectivities.


Subject(s)
Lactones/chemical synthesis , Quinolines/chemical synthesis , Catalysis , Hydrogenation , Lactones/chemistry , Molecular Structure , Quinolines/chemistry , Stereoisomerism
10.
Eur J Med Chem ; 46(1): 31-8, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21094564

ABSTRACT

In this work we reported the synthesis and evaluation of Mycobacterium tuberculosis activities in vitro of a series of twenty five ferrocenyl derivatives: ferrocenyl amides derived from nicotinamide and pyrazinamide, ferrocenyl pyridinyl, quinolyl and acridinylhydrazones. In particular ferrocenyl acylhydrazones 7 and 8 and ferrocenylquinoxaline amide 57 showed interesting antimycobacterial activities.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Ferrous Compounds/chemical synthesis , Ferrous Compounds/pharmacology , Anti-Bacterial Agents/chemistry , Ferrous Compounds/chemistry , Metallocenes , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Niacinamide/chemistry , Pyrazinamide/chemistry
12.
J Med Chem ; 49(15): 4707-14, 2006 Jul 27.
Article in English | MEDLINE | ID: mdl-16854077

ABSTRACT

A new therapeutic approach to malaria led to the discovery of ferroquine (FQ, SR97276). To assess the importance of the linkage of the ferrocenyl group to a 4-aminoquinoline scaffold, two series of 4-aminoquinolines, structurally related to FQ, were synthesized. Evaluation of antimalarial activity, physicochemical parameters, and the beta-hematin inhibition property indicate that the ferrocene moiety has to be covalently flanked by a 4-aminoquinoline and an alkylamine. Current data reinforced our choice of FQ as a drug candidate.


Subject(s)
Antimalarials/chemical synthesis , Chloroquine/chemistry , Ferrous Compounds/chemical synthesis , Quinolines/chemical synthesis , Aminoquinolines , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Ferrous Compounds/chemistry , Ferrous Compounds/pharmacology , Hemeproteins/antagonists & inhibitors , Hemeproteins/chemical synthesis , Metallocenes , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship
13.
Malar J ; 5: 11, 2006 Feb 07.
Article in English | MEDLINE | ID: mdl-16464254

ABSTRACT

BACKGROUND: Ferroquine (FQ), or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. FQ is a unique organometallic compound designed to overcome the chloroquine (CQ) resistance problem. FQ revealed to be equally active on CQ-sensitive and CQ-resistant Plasmodium falciparum laboratory strains and field isolates. FQ is also curative on rodent malaria parasites. As FQ will be tested in patients, the potential for resistance to this drug was evaluated. METHODS: The relationship between CQ-resistant transporter gene genotype and susceptibility to FQ were studied in 33 Cambodian P. falciparum field isolates previously studied for their in vitro response to CQ. In parallel, the ability of the CQ-resistant strain W2, to become resistant to FQ under drug pressure was assessed. RESULTS: The IC50 values for FQ in field isolates were found to be unrelated to mutations occurring in the P. falciparum chloroquine resistance transporter (PfCRT) or to the level of expression of the corresponding mRNA. In vitro, under a drug pressure of 100 nM of FQ, transient survival was observed in only one of two experiments. CONCLUSION: Field isolates studies and experimental drug pressure experiments showed that FQ overcomes CQ resistance, which reinforces the potential of this compound as a new antimalarial drug.


Subject(s)
Aminoquinolines/pharmacology , Antimalarials/pharmacology , Drug Resistance/genetics , Ferrous Compounds/pharmacology , Membrane Transport Proteins/genetics , Plasmodium falciparum/drug effects , Protozoan Proteins/genetics , Amino Acid Sequence , Aminoquinolines/chemistry , Animals , Antimalarials/chemistry , Blood Cells/parasitology , Cells, Cultured , Chloroquine/chemistry , Chloroquine/pharmacology , Ferrous Compounds/chemistry , Flow Cytometry/methods , Genetic Variation , Inhibitory Concentration 50 , Metallocenes , Parasitic Sensitivity Tests , Plasmodium falciparum/genetics
14.
Drug Metab Dispos ; 34(4): 667-82, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16415117

ABSTRACT

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.


Subject(s)
Aminoquinolines/metabolism , Antimalarials/metabolism , Ferrous Compounds/metabolism , Hepatocytes/enzymology , Microsomes, Liver/enzymology , Plasmodium falciparum/drug effects , Aminoquinolines/pharmacology , Animals , Antimalarials/pharmacology , Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Cells, Cultured , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Dogs , Ferrous Compounds/pharmacology , Humans , Isoenzymes/genetics , Isoenzymes/metabolism , Macaca fascicularis , Male , Metallocenes , Mice , Oxidation-Reduction , Rats , Rats, Sprague-Dawley , Recombinant Proteins/metabolism , Species Specificity
15.
Bioorg Med Chem ; 14(5): 1294-302, 2006 Mar 01.
Article in English | MEDLINE | ID: mdl-16242338

ABSTRACT

Fourteen ferrocenyl aminohydroxynaphthoquinones, analogues of atovaquone, were synthesized from the hydroxynaphthoquinone core. These novel atovaquone derivatives were tested for their in vitro activity against two apicomplexan parasites of medical importance, Toxoplasma gondii and Plasmodium falciparum, including resistant strains to atovaquone (T. gondii) and chloroquine (P. falciparum). Three of these ferrocenic atovaquone derivatives composed of the hydroxynaphthoquinone core plus an amino-ferrocenic group and an aliphatic chain with 6-8 carbon atoms were found to be significantly active against T. gondii. Moreover, these novel compounds were also effective against the atovaquone-resistant strain of T. gondii (Ato(R)).


Subject(s)
Antiprotozoal Agents/pharmacology , Apicomplexa/drug effects , Naphthoquinones/pharmacology , Plasmodium falciparum/drug effects , Toxoplasma/drug effects , Animals , Antiprotozoal Agents/chemical synthesis , Binding Sites , Ferrous Compounds/chemistry , Models, Chemical , Naphthoquinones/chemical synthesis
17.
Bioorg Med Chem Lett ; 15(4): 1239-41, 2005 Feb 15.
Article in English | MEDLINE | ID: mdl-15686950

ABSTRACT

Several strychnobrasiline derivatives have been synthesized to overcome the lack of in vivo reversal activity of the parent compound. In the present study, N(a)-deacetyl-ferrocenoyl-strychnobrasiline was synthesized by condensing N(a)-deacetyl-strychnobrasiline with ferrocenic acid previously treated with oxalyl chloride. While the in vitro antiplasmodial activity of the test compound (IC(50)=4.83 microg/mL) was increased 15-fold compared to that of strychnobrasiline, and the in vitro enhancing activity was found to be similar to that of the parent compound, the compound was devoid of any in vivo potentiating effect, and an antagonistic effect was even observed at higher doses. Based on the overall results on the hemisynthesis of strychnobrasiline derivatives for better reversal activity, this strategy has appeared to be of little value for useful drugs.


Subject(s)
Alkaloids/chemical synthesis , Antimalarials/chemical synthesis , Chloroquine/pharmacology , Ferric Compounds/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Alkaloids/pharmacokinetics , Alkaloids/pharmacology , Animals , Antimalarials/pharmacology , Blood/parasitology , Drug Interactions , Drug Resistance/drug effects , Ferric Compounds/pharmacokinetics , Ferric Compounds/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Inhibitory Concentration 50 , Plasmodium falciparum/drug effects , Structure-Activity Relationship
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