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1.
ACS Omega ; 4(26): 22214-22227, 2019 Dec 24.
Article in English | MEDLINE | ID: mdl-31891105

ABSTRACT

This study concerns the development of folic acid (FA)-functionalized iron oxide condensed colloidal magnetic clusters for a more selective delivery of doxorubicin (DOX) to tumor cancer cells overexpressing the folate receptor. Alginate-coated condensed magnetic nanoparticles (co-MIONs) were synthesized via an alkaline precipitation method of an iron precursor in the presence of sodium alginate. Poly(ethylene glycol) (OH-PEG-NH2) was conjugated to the carboxylic acid end group of alginate and folic acid (FA) was conjugated to the hydroxyl terminal group of PEG to produce folate-functionalized, pegylated co-MIONS (Mag-Alg-PEG-FA). The physicochemical properties of nanoparticles were fully characterized. DOX was loaded on the nanoparticles, and the cellular uptake and anticancer efficacy of the nanoparticles were examined in cancer cell lines expressing and not expressing the folate receptor. The biocompatibility of the carrier (blank nanoparticles) was also evaluated by cytocompatibility and hemocompatibility experiments. The nanoparticles exhibited sustained DOX release in aqueous buffers and biorelevant media, which was responsive to pH and external alternating current magnetic fields. The effect of the magnetic field on DOX percentage release appeared to be independent of the timing (onset time) of magnetic field application, providing flexibility to the magnetic control of drug release from the nanoparticles. The blank nanoparticles were not cytotoxic and did not cause hemolysis. The DOX-loaded and FA-functionalized nanoparticles exhibited increased uptake and caused increased apoptosis and cytotoxicity against the MDA-MB-231 cell line, expressing the folate receptor, compared to the MCF-7 cell line, not expressing the folate receptor. The application of a 0.5 T magnetic field during incubation of the nanoparticles with the cancer cells increased the cellular uptake and cytotoxicity of the nanoparticles. The obtained results indicate the potential of the folate-functionalized, pegylated co-MIONS for a more efficacious DOX delivery to cancer cells of solid tumors.

2.
Eur J Med Chem ; 93: 281-90, 2015 Mar 26.
Article in English | MEDLINE | ID: mdl-25703296

ABSTRACT

Novel 1-(2-aryl-2-adamantyl)piperazine derivatives have been synthesized and evaluated in vitro for their antitumor properties against HeLa cervical carcinoma, MDA MB 231 breast cancer, MIA PaCa2 pancreatic cancer, and NCI H1975 non-small cell lung cancer. The parent piperazine 6 was found to exhibit a reasonable activity toward the HeLa and MDA MB 231 tumor cell lines (IC50= 9.2 and 8.4 µΜ, respectively). Concurrent benzene ring C4-fluorination and piperidine acetylation of the piperazino NH of compound 6 resulted in the most active compound 13 of the series in both of the above cell lines (IC50=8.4 and 6.8 µΜ, respectively). Noticeably, compounds 6 and 13 exhibited a significantly low cytotoxicity level over the normal human cells HUVEC (Human Umbilical Vein Endothelial Cells) and NHDF (Normal Human Dermal Fibroblasts).


Subject(s)
Adamantane/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Antineoplastic Agents/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , HeLa Cells , Humans , Piperazine , Piperazines/metabolism , Receptors, sigma/metabolism
3.
J Med Chem ; 54(14): 5250-4, 2011 Jul 28.
Article in English | MEDLINE | ID: mdl-21542562

ABSTRACT

We describe novel acetohydroxamic acid derivatives with potent activity against cultured bloodstream-form Trypanosoma brucei and selectivity indices of >1000. These analogues were derived from conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds by attaching acetohydroxamic acid moieties to the imidic nitrogen. Optimal activity was achieved by placing benzyl groups adjacent to the basic nitrogen of the 2,6-DKP core. S-Enantiomer 7d was the most active derivative against T. brucei (IC(50) = 6.8 nM) and T. cruzi (IC(50) = 0.21 µM).


Subject(s)
Hydroxamic Acids/chemical synthesis , Piperazines/chemical synthesis , Spiro Compounds/chemical synthesis , Trypanocidal Agents/chemical synthesis , Animals , Cell Line , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Molecular Conformation , Parasitic Sensitivity Tests , Piperazines/chemistry , Piperazines/pharmacology , Rats , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma cruzi/drug effects
4.
Bioorg Chem ; 38(6): 247-51, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20926112

ABSTRACT

Spiro[piperidine-2,2'-adamantane] 4 is one of the most potent synthetic anti-influenza A aminoadamantanes or other cage structure amines tested so far. Based on previous results Tataridis et al. (2007) [5h] which demonstrate the boost of in vitro potency by the presence of an additional amino group, we examined whether the incorporation of a second amino group into this heterocycle would increase the anti-influenza A virus activity. The new synthetic molecules 5-7 are capable of forming two hydrogen bonds within the receptor. We identified the diamino derivatives 5 and 6, which are active against influenza A H3N2 virus although less potent than amantadine and its equipotent spiropiperidine 4.


Subject(s)
Adamantane/analogs & derivatives , Adamantane/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Influenza A Virus, H3N2 Subtype/drug effects , Piperazines/chemistry , Piperazines/pharmacology , Adamantane/chemical synthesis , Animals , Antiviral Agents/chemical synthesis , Cell Line , Humans , Influenza, Human/drug therapy , Orthomyxoviridae Infections/drug therapy , Piperazines/chemical synthesis , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacology
5.
Bioorg Med Chem Lett ; 17(3): 692-6, 2007 Feb 01.
Article in English | MEDLINE | ID: mdl-17113287

ABSTRACT

We examined whether the incorporation of a second amino group into the 1-aminoethyl pharmacophore of rimantadine 2 and into the piperidine pharmacophore of the heterocyclic rimantadine 4 was compatible with anti-influenza virus A activity. The new synthetic molecules are capable of forming two hydrogen bonds within the receptor. We identified molecules 8 and 16, bearing the adamantyl and 1,2-diaminoethyl groups, which are equipotent to rimantadine 2 bearing the adamantyl and 1-aminoethyl pharmacophore groups. Interestingly, diamino compound 16 is a 4-fold more potent inhibitor than its parent monoamino heterocyclic rimantadine 4 propably because of additional hydrogen bonding interactions with the M2 protein receptor.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Influenza A virus/drug effects , Rimantadine/analogs & derivatives , Rimantadine/chemical synthesis , Amination , Animals , Cell Line , Dogs , Indicators and Reagents , Influenza A Virus, H3N2 Subtype/drug effects , Magnetic Resonance Spectroscopy , Methylation , Rimantadine/pharmacology , Structure-Activity Relationship , Virus Replication
6.
Bioorg Med Chem ; 14(10): 3341-8, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16439137

ABSTRACT

2-(1-Adamantyl)-2-methyl-pyrrolidines 3 and 4, 2-(1-adamantyl)-2-methyl-azetidines 5 and 6, and 2-(1-adamantyl)-2-methyl-aziridines 7 and 8 were synthesized and tested for their antiviral activity against influenza A. Parent molecules 3, 5, and 7 contain the alpha-methyl-1-adamantan-methanamine 2 pharmacophoric moiety (rimantadine). The ring size effect on anti-influenza A activity was investigated. Pyrrolidine 3 was the most potent anti-influenza virus A compound, 9-fold more potent than rimantadine 2, 27-fold more potent than amantadine 1, and 22-fold more potent than ribavirin. Azetidines 5 and 6 were both markedly active against influenza A H2N2 virus, 10- to 20-fold more potent than amantadine. Aziridine 7 was almost devoid of any activity against H2N2 virus but exhibited borderline activity against H3N2 influenza A strain. Thus, it appears that changing the five-, to four- to a three-membered ring results in a drop of activity against influenza A virus.


Subject(s)
Antiviral Agents/pharmacology , Heterocyclic Compounds/pharmacology , Influenza A Virus, H2N2 Subtype/drug effects , Influenza A Virus, H3N2 Subtype/drug effects , Rimantadine/analogs & derivatives , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cells, Cultured , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Lethal Dose 50 , Microbial Sensitivity Tests , Rimantadine/pharmacology
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