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1.
J Med Chem ; 64(7): 3897-3910, 2021 04 08.
Article in English | MEDLINE | ID: mdl-33764059

ABSTRACT

Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure-activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors. Several highly active azaphosphinanes display attractive properties suitable for further in vivo efficacy studies in thrombosis models.


Subject(s)
Aza Compounds/pharmacology , Carboxypeptidase B2/antagonists & inhibitors , Cyclic P-Oxides/pharmacology , Fibrinolytic Agents/pharmacology , Phosphinic Acids/pharmacology , Protease Inhibitors/pharmacology , Animals , Aza Compounds/chemical synthesis , Aza Compounds/metabolism , Carboxypeptidase B2/metabolism , Catalytic Domain , Cyclic P-Oxides/chemical synthesis , Cyclic P-Oxides/metabolism , Fibrinolysis/drug effects , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/metabolism , Humans , Male , Molecular Docking Simulation , Molecular Structure , Phosphinic Acids/chemical synthesis , Phosphinic Acids/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Protein Binding , Rats, Sprague-Dawley , Structure-Activity Relationship
2.
Chem Commun (Camb) ; 54(3): 299-302, 2018 Jan 02.
Article in English | MEDLINE | ID: mdl-29239411

ABSTRACT

The far-red emissive fluorescent probe CaPF-1 based on a phospha-fluorescein scaffold enables the detection of cytosolic calcium ions in living cells. The probe can be excited in the red region (λabs = 636 nm) and exhibits a sufficiently high fluorescence turn-on response in the far-red region (λem = 663 nm) upon complexation with calcium ions. The hydrophilic and anionic characteristics of this phospha-fluorescein fluorophore allowed the cytosolic localization of CaPF-1. Moreover, it was possible to visualize histamine-induced calcium oscillation in HeLa cells using CaPF-1.


Subject(s)
Calcium/analysis , Cyclic P-Oxides/pharmacology , Fluoresceins/pharmacology , Fluorescent Dyes/pharmacology , Calcium/metabolism , Cyclic P-Oxides/chemical synthesis , Cyclic P-Oxides/chemistry , Fluoresceins/chemical synthesis , Fluoresceins/chemistry , Fluorescence , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , HeLa Cells , Histamine/metabolism , Humans , Hydrogen-Ion Concentration , Microscopy, Confocal , Molecular Imaging , Optical Imaging , Receptors, Histamine H1/metabolism
3.
Chem Commun (Camb) ; 51(59): 11880-3, 2015 Jul 28.
Article in English | MEDLINE | ID: mdl-26110470

ABSTRACT

We disclose the development of a ratiometric fluorescent probe based on a benzophosphole P-oxide and its application for the detection of intracellular Na(+) ions. Excitation by visible light induced red emission from this probe in water, which was subjected to a hypsochromic shift upon complexation with Na(+). Based on this change, a ratiometric analysis enabled us to visualise changes in the Na(+) concentration in living mammalian cells.


Subject(s)
Cyclic P-Oxides/chemistry , Fluorescent Dyes/chemistry , Oxides/chemistry , Sodium/analysis , Cyclic P-Oxides/chemical synthesis , Fluorescent Dyes/chemical synthesis , HeLa Cells , Humans , Ions/analysis , Molecular Structure , Oxides/chemical synthesis
4.
J Am Chem Soc ; 135(7): 2474-7, 2013 Feb 20.
Article in English | MEDLINE | ID: mdl-23369026

ABSTRACT

A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.


Subject(s)
Cyclic P-Oxides/chemical synthesis , Phosphines/chemical synthesis , Cyclic P-Oxides/chemistry , Ligands , Molecular Structure , Phosphines/chemistry , Stereoisomerism
5.
J Med Chem ; 55(5): 2196-211, 2012 Mar 08.
Article in English | MEDLINE | ID: mdl-22268526

ABSTRACT

This paper reports the design and the synthesis of a new family of compounds, the phostines, belonging to the [1,2]oxaphosphinane family. Twenty-six compounds have been screened for their antiproliferative activity against a large panel of NCI cancer cell lines. Because of its easy synthesis and low EC(50) value (500 nM against the C6 rat glioma cell line), compound 3.1a was selected for further biological study. Moreover, the specific biological effect of 3.1a on the glioblastoma phylogenetic cluster from the NCI is dependent on its stereochemistry. Within that cluster, 3.1a has a higher antiproliferative activity than Temozolomide and is more potent than paclitaxel for the SF295 and SNB75 cell lines. In constrast with paclitaxel and vincristine, 3.1a is devoid of astrocyte toxicity. The original activity spectrum of 3.1a on the NCI cancer cell line panel allows the development of this family for use in association with existing drugs, opening new therapeutic perspectives.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclic P-Oxides/chemical synthesis , Organophosphonates/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Astrocytes/cytology , Astrocytes/drug effects , Brain Neoplasms/drug therapy , Cell Count , Cell Line, Tumor , Cell Survival/drug effects , Cyclic P-Oxides/chemistry , Cyclic P-Oxides/pharmacology , Drug Screening Assays, Antitumor , Glioblastoma/drug therapy , Humans , Organophosphonates/chemistry , Organophosphonates/pharmacology , Phosphorous Acids , Rats , Stereoisomerism , Structure-Activity Relationship
6.
Nucleosides Nucleotides Nucleic Acids ; 30(11): 886-96, 2011 Nov.
Article in English | MEDLINE | ID: mdl-22060553

ABSTRACT

In order to support bioanalytical LC/MS method development and plasma sample analysis in preclinical and clinical studies of the anti-hepatitis C-virus nucleotides, PSI-7977 and PSI-352938, the corresponding stable isotope labeled forms were prepared. These labeled compounds were prepared by addition reaction of the freshly prepared Grignard reagent (13)CD(3)MgI to the corresponding 2 '-ketone nucleosides followed by fluorination of the resulting carbinol with DAST. As expected, these 2 '-C-(trideuterated-(13)C-methyl) nucleotide prodrugs showed similar anti-HCV activity to that of the corresponding unlabeled ones.


Subject(s)
Antiviral Agents/chemistry , Cyclic P-Oxides/chemistry , Hepacivirus/drug effects , Nucleosides/chemistry , Prodrugs/chemistry , Uridine Monophosphate/analogs & derivatives , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cyclic P-Oxides/chemical synthesis , Cyclic P-Oxides/pharmacology , Halogenation , Hepatitis C/drug therapy , Humans , Isotope Labeling/methods , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Sofosbuvir , Uridine Monophosphate/chemical synthesis , Uridine Monophosphate/chemistry , Uridine Monophosphate/pharmacology
8.
J Org Chem ; 76(10): 3782-90, 2011 May 20.
Article in English | MEDLINE | ID: mdl-21469736

ABSTRACT

PSI-352938 is a novel 2'-deoxy-2'-α-fluoro-2'-ß-C-methyl 3',5'-cyclic phosphate nucleotide prodrug currently under investigation for the treatment of hepatitis C virus (HCV) infection. PSI-352938 demonstrated superior characteristics in vitro that include broad genotype coverage, superior resistance profile, and high levels of active triphosphate in vivo in the liver compared to our first and second generation nucleoside inhibitors of this class. Consequently, PSI-352938 was selected for further development and an efficient and scalable synthesis was sought to support clinical development. We report an improved, diastereoselective synthesis of a key 1'-ß-nucleoside intermediate 13 via S(N)2 displacement of 1-α-bromo ribofuranose sugar 16 with the potassium salt of 6-chloro-2-amino purine and an efficient method to prepare cis-Rp cyclic phosphate (PSI-352938) in a highly stereoselective manner without any chromatographic purification. The 1-α-bromo sugar 16 was stereospecifically prepared from the corresponding 1-ß-lactol in high yield under mild bromination conditions using CBr(4)/PPh(3) (Appel reaction). The desired cis-Rp 3',5'-cyclic phosphate construction was accomplished using isopropyl phosphorodichloridate readily obtained from POCl(3) and isopropyl alcohol. The base combination of Et(3)N/NMI was identified as a key factor for producing PSI-352938 as the major (>95%) diastereomer (cis-Rp) in high yield after the final cyclization step. The current route described in this article was successfully used to produce PSI-352938 on multikilogram scale.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Cyclic P-Oxides/chemistry , Cyclic P-Oxides/chemical synthesis , Hepacivirus/drug effects , Nucleosides/chemistry , Nucleosides/chemical synthesis , Prodrugs/chemistry , Prodrugs/chemical synthesis , Antiviral Agents/pharmacology , Cyclic P-Oxides/pharmacology , Cyclization , Nucleosides/pharmacology , Prodrugs/pharmacology , Stereoisomerism , Substrate Specificity
9.
Bioorg Med Chem Lett ; 20(19): 5943-6, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20801031

ABSTRACT

4-Bromo-3,4-dimethyl-1-phenyl-2-phospholene 1-oxide (3c) was first synthesized from 3,4-dimethyl-1-phenyl-2-phospholene 1-oxide (2c) by a bromo-radical substitution reaction occurred at C-4 position by N-bromosuccinimide and 2,2'-azobisisobutyronitrile. The novel phospha sugar analogue 3c exerted high anti-proliferative effect on U937 cells evaluated by MTT in vitro methods and was much more efficient than that of Gleevec, which is known as a molecule targeting chemotherapeutical agent. The substitution of 2-phospholenes at C-3 and C-4 position with methyl groups as well as 4-bromo substituent suggests a good anti-proliferative effect.


Subject(s)
Antineoplastic Agents/chemistry , Cyclic P-Oxides/chemical synthesis , Heterocyclic Compounds/chemistry , Organophosphorus Compounds/chemical synthesis , Phosphorus/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Benzamides , Cell Line, Tumor , Cyclic P-Oxides/chemistry , Cyclic P-Oxides/toxicity , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/toxicity , Humans , Imatinib Mesylate , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/toxicity , Piperazines/toxicity , Pyrimidines/toxicity
10.
Invest New Drugs ; 28(4): 381-91, 2010 Aug.
Article in English | MEDLINE | ID: mdl-19436953

ABSTRACT

Here, we synthesized two phospha sugar derivatives, 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (TMPP) and 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (DMPP) by reacting 3-methyl-1-phenyl-2-phospholene 1-oxide with bromine, and investigated their potential as antileukemic agents in cell lines. Both agents showed inhibitory effects on leukemia cell proliferation, with mean IC(50) values of 6.25 micromol/L for TMPP and 23.7 micromol/L for DMPP, indicating that inhibition appeared to be dependent on the number of bromine atoms in the structure. Further, TMPP at 10 micromol/L and DMPP at 20 micromol/L induced G2/M cell cycle block in leukemia cells, and TMPP at 20 micromol/L induced apoptosis in these cells. TMPP treatment effected a reduction in both cell cycle progression signals (FoxM1, KIS, Cdc25B, Cyclin D1, Cyclin A, and Aurora-B) and tumor cell survival (p27(Kip1) and p21(Cip1)), as well as induced the activation of caspase-3 and -9. Further, treatment with TMPP significantly reduced the viability of AML specimens derived from AML patients, but only slightly reduced the viability of normal ALDH(hi) progenitor cells. We also observed that FoxM1 mRNA was overexpressed in AML cells, and treatment with TMPP reduced FoxM1 mRNA expression in AML cells. Here, we report on the synthesis of TMPP and DMPP and demonstrate that these agents hinder proliferation of leukemia cells by FoxM1 suppression, which leads to G2/M cell cycle block and subsequent caspase-3-dependent apoptosis in acute leukemia cells. These agents may facilitate the development of new strategies in targeted antileukemic therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Cyclic P-Oxides/pharmacology , Drug Screening Assays, Antitumor/methods , Leukemia, Myeloid, Acute/drug therapy , Leukemia/drug therapy , Organophosphorus Compounds/pharmacology , Adult , Aged , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Caspase 3/metabolism , Caspase 9/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cyclic P-Oxides/chemical synthesis , Cyclic P-Oxides/chemistry , Forkhead Box Protein M1 , Forkhead Transcription Factors/metabolism , Humans , Middle Aged , Organophosphorus Compounds/chemical synthesis
11.
Bioorg Med Chem Lett ; 14(20): 5067-70, 2004 Oct 18.
Article in English | MEDLINE | ID: mdl-15380200

ABSTRACT

5-Carboxamido-1,3,2-dioxaphosphorinanes have been identified as potent inhibitors of microsomal triglyceride-transfer protein. The 1,3,2-dioxaphosphorine functionality acted as a neutral and stable replacement for piperidine and piperidine N-oxide.


Subject(s)
Amides/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Cyclic P-Oxides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Cricetinae , Cyclic P-Oxides/chemistry , Cyclic P-Oxides/pharmacology , Humans , In Vitro Techniques , Male , Stereoisomerism , Structure-Activity Relationship
12.
Org Lett ; 4(14): 2357-60, 2002 Jul 11.
Article in English | MEDLINE | ID: mdl-12098246

ABSTRACT

[reaction: see text] A double diastereotopic differentiation strategy on a phosphonoacetate template is described. The approach utilizes Rh(2)(OAc)(4)-catalyzed intramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate. The olefinic diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group selectivity is dictated by the chiral auxiliary. This approach is being developed as an effective method to access bicyclic P-chiral phosphonates.


Subject(s)
Cyclic P-Oxides/chemical synthesis , Cyclopropanes/chemistry , Catalysis , Crystallography, X-Ray , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Stereoisomerism
13.
Chem Pharm Bull (Tokyo) ; 40(9): 2370-6, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1446357

ABSTRACT

Six optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl 5-(4,6-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (NIP-101, 1.2HCl.2H2O), a potent calcium antagonist, were successfully prepared by using optically active (2R,4R)-(-)- and (2S,4S)-(+)-2,4-pentanediols, and cis-2,4-pentanediol and optically active (S)-(+)-2-methoxy-2-phenylethanol. Their proton nuclear magnetic resonance investigations demonstrate that the 1,3,2-dioxaphosphorinane group is conformationally constrained around the C-P bond. Calcium-antagonistic and hypotensive activities of the optical isomers were examined and found to depend mainly on the absolute configuration at a stereogenic center in the 1,4-dihydropyridine ring rather than the configuration of the 1,3,2-dioxaphosphorinane moiety.


Subject(s)
Antihypertensive Agents/chemical synthesis , Calcium Channel Blockers/chemical synthesis , Cyclic P-Oxides/chemical synthesis , Nicotinic Acids/chemical synthesis , Animals , Antihypertensive Agents/pharmacology , Calcium Channel Blockers/pharmacology , Cyclic P-Oxides/pharmacology , Nicotinic Acids/pharmacology , Rats , Rats, Inbred SHR , Stereoisomerism
14.
Cancer Res ; 50(10): 3055-61, 1990 May 15.
Article in English | MEDLINE | ID: mdl-1970752

ABSTRACT

Four pyridine analogues and their dihydropyridine counterparts were examined for their ability to reverse drug resistance in a multidrug-resistant human carcinoma cell line, KB-C2. Two pyridine analogues were more able to reverse drug resistance than their dihydropyridine counterparts. The other two pyridine analogues had an effect on drug resistance similar to their dihydropyridine counterparts. The calcium channel-blocking activity of all the pyridine analogues was considerably lower than that of the dihydropyridine analogues. Of the pyridine analogues, 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl 5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4 -(3- nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) was the most effective in reversing multidrug resistance. PAK-104P (1 and 5 microM) completely reversed the drug resistance in KB-8-5 and KB-C2 cells, respectively. The reversing effect of PAK-104P was greater than that of other multidrug resistance-reversing agents, cepharanthine, verapamil, nimodipine, and nicardipine. PAK-104P at 1 microM increased about 10-fold the accumulation of vinblastine in KB-C2 cells, whereas verapamil at the same concentration increased the accumulation about 2-fold. The inhibition of [3H]azidopine photolabeling of P-glycoprotein by the pyridine and dihydropyridine analogues except 2-[methyl(phenyl-methyl)amino]ethyl 4-(2-chlorophenyl)-5-(4-methyl-1,3,2-dioxaphosphorinan-2-yl)-1,4-d ihydro-2,6- dimethyl-3-pyridinecarboxylate P-oxide correlated with the reversing of drug resistance by the analogues. Some newly synthesized pyridine analogues seemed to have lower calcium channel-blocking activity and more potent resistance-reversing ability than verapamil and other calcium channel blockers.


Subject(s)
Calcium Channel Blockers , Cyclic P-Oxides/pharmacology , Drug Resistance , Nicotinic Acids/pharmacology , Pyridines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Biological Transport/drug effects , Calcium/metabolism , Chemical Phenomena , Chemistry , Cyclic P-Oxides/chemical synthesis , Cytotoxins , Dihydropyridines/chemical synthesis , Dihydropyridines/pharmacology , Electric Conductivity , Humans , Membrane Glycoproteins/metabolism , Nicotinic Acids/chemical synthesis , Pyridines/chemical synthesis , Structure-Activity Relationship , Tumor Cells, Cultured , Vinblastine/metabolism
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