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1.
ACS Med Chem Lett ; 15(3): 418-422, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38505859

ABSTRACT

Herein, we report the design, the synthesis, and the study of novel triphenyl phosphonium-based nucleoside conjugates. 2'-Deoxycytidine was chosen as nucleosidic cargo, as it allows the introduction of fluorescein on the exocyclic amine of the nucleobase and grafting of the vector was envisaged through the formation of a biolabile ester bond with the hydroxyl function at the 5'-position. Compound 3 was identified as a potential nucleoside prodrug, showing ability to be internalized efficiently into cells and to be co-localized with mitochondria.

2.
Curr Mol Pharmacol ; 15(6): 883-894, 2022.
Article in English | MEDLINE | ID: mdl-34649495

ABSTRACT

BACKGROUND: The development of small molecules as cancer treatments is still of both interest and importance. OBJECTIVE: Having synthesized and identified the initial cytotoxic activity of a series of chemically related N-(9H-purin-6-yl) benzamide derivatives, we continued their evaluation on cancer cell models. We also synthesized water-soluble prodrugs of the main compound and performed in vivo experiments. METHOD: We used organic chemistry to obtain compounds of interest and prodrugs. The biological evaluation included MTT assays, synergy experiments, proliferation assays by CFSE, cell cycle distribution and in vivo antitumoral activity. RESULTS: Our results show activities on cancer cell lines ranging from 3-39 µM for the best compounds, with both induction of apoptosis and decrease in cell proliferation. Two compounds evaluated in vivo showed weak antitumoral activity. In addition, the lead compound and its prodrug had a synergistic activity with the nucleoside analogue fludarabine in vitro and in vivo. CONCLUSION: Our work allowed us to gain better knowledge on the activity of N-(9H-purin-6-yl) benzamide derivatives and showed new examples of water-soluble prodrugs. More research is warranted to decipher the molecular mechanisms of the molecules.


Subject(s)
Antineoplastic Agents , Neoplasms , Prodrugs , Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Humans , Prodrugs/pharmacology , Structure-Activity Relationship , Water
3.
Eur J Med Chem ; 168: 28-44, 2019 Apr 15.
Article in English | MEDLINE | ID: mdl-30798051

ABSTRACT

The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200 µM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58 mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter.


Subject(s)
5'-Nucleotidase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Purines/pharmacology , 5'-Nucleotidase/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Models, Molecular , Molecular Structure , Purines/chemical synthesis , Purines/chemistry , Structure-Activity Relationship
4.
J Med Chem ; 58(24): 9680-96, 2015 Dec 24.
Article in English | MEDLINE | ID: mdl-26599519

ABSTRACT

We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents.


Subject(s)
5'-Nucleotidase/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Benzoates/chemical synthesis , Benzoates/chemistry , Benzoates/pharmacology , Binding Sites , Cell Line, Tumor , Computer Simulation , Databases, Chemical , Drug Screening Assays, Antitumor , Drug Synergism , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Docking Simulation , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Naphthalenes/pharmacology , Purines/chemical synthesis , Purines/chemistry , Purines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 13(24): 4473-5, 2003 Dec 15.
Article in English | MEDLINE | ID: mdl-14643349

ABSTRACT

The detailed study of the 1,3-dihydrobenzo[c]furan derivative of thymine is reported. The lack of anti-HIV activity of this compound in cell culture experiments is shown to be related to the inability of the corresponding 5'-triphosphate derivative to interact efficiently with the reverse transcriptase.


Subject(s)
Benzofurans/chemistry , Benzofurans/pharmacology , Thymine/analogs & derivatives , Anti-HIV Agents/chemistry , Benzofurans/chemical synthesis , Half-Life , Hydrogen-Ion Concentration , Nucleosides , Stavudine/chemistry , Structure-Activity Relationship
6.
J Med Chem ; 46(21): 4564-71, 2003 Oct 09.
Article in English | MEDLINE | ID: mdl-14521418

ABSTRACT

The synthesis and in vitro anti-HIV activity of phosphoramidate diester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing one S-pivaloyl-2-thioethyl (tBuSATE) group and various amino residues are reported. These compounds were obtained from an H-phosphonate strategy using an amidative oxidation step. Most of these derivatives appeared to inhibit HIV-1 replication, with EC(50) values at micromolar concentration in thymidine kinase-deficient (TK-) cells, revealing a less restrictive intracellular decomposition process than previously reported for other phosphoramidate prodrugs. The proposed decomposition pathway of this new series of mixed pronucleotides may successively involve an esterase and a phosphoramidase hydrolysis.


Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Cell Line , HIV-1/drug effects , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Thymidine Kinase/genetics , Thymidine Kinase/metabolism , Virus Replication/drug effects
8.
Bioorg Med Chem Lett ; 12(2): 265-6, 2002 Jan 21.
Article in English | MEDLINE | ID: mdl-11755368

ABSTRACT

The bis(S-pivaloyl-2-thioethyl) phosphotriester derivative of 9-(4'-hydroxy-1',2'-butadienyl)adenine (adenallene) was synthesized. This mononucleotide prodrug proved to be more effective than the parent nucleoside in inhibiting HIV-1 replication in several human T4 lymphoblastoid cell lines.


Subject(s)
Adenine/analogs & derivatives , Adenine/pharmacology , HIV-1/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Adenine/chemistry , Cell Line , Esters , HIV-1/physiology , Humans , Reverse Transcriptase Inhibitors/chemistry , Virus Replication/drug effects
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