Methylphosphonate Derivatives Research Articles

ULTRASOUND-ASSISTED SYNTHESIS AND DOCKING STUDY OF NOVEL CHROMONE-THIADIAZOLE INTEGRATED PHOSPHONATE DERIVATIVES TARGETING TOPOISOMERASE II AS ANTICANCER AGENTS

Objective: The present studies discuss the anticancer activity of different topoisomerase II inhibitors with docking study.
 Methods: The work reports the synthesis of novel diethyl (4-oxo-4H-chromen-3-yl)(5-substituted phenyl-1,3,4-thiadiazol-2-ylamino)methyl phosphonate derivatives 6(a-j). They were synthesized through one-pot three-component Kabachnik-Fields reaction by using ultrasonicator processor, at room temperature in presence of Zirconium oxychloride (ZrOCl2).
 Results: The structures of the synthesized compounds were confirmed by spectral analysis. The synthesized derivatives 6(a-j) were evaluated for their in vitro anticancer activity against human cancer cell lines such as DU 145 (Human Prostate Cancer) and MCF-7 (Breast cancer) and also on non-tumor cell lines such as MCF-10 (normal breast epithelial cell) by MTT assay. From the anticancer screening results data, compound 6e was found to be the most potent anticancer compound among the synthesized compounds against MCF-7 and DU 145 cancer cell lines with IC50 value of 2.97 µM and 3.11 µM, respectively. The compound 6h has shown cell cycle arrest at G2/M phase, along with the decrease of cells at G0/G1 phage. The compound 6h was able to induce apoptosis in DU 145 cell lines. The synthesized compounds 6(a-j) were further evaluated for their topoisomerase II inhibitory activity.
 Conclusion: The anticancer screening result and MTT assay, along with the docking study shows that the synthesised derivative are active anticancer agent against MCF-10, DU-145 and MCF-7 cell line.

Investigation of some diethyl (4-(dimethylamino)-2,5-dihydro-2,5-dioxo-1-phenyl-1H-pyrrol-3-yl)(hydroxy)methylphosphonate derivatives for In silico pharmacokinetic profile and In vitro anticancer activity

Investigation of some diethyl (4-(dimethylamino)-2,5-dihydro-2,5-dioxo-1-phenyl-1H-pyrrol-3-yl)(hydroxy)methylphosphonate derivatives for In silico pharmacokinetic profile and In vitro anticancer activity

Synthesis of novel α-aminophosphonates by methanesulfonic acid catalyzed Kabachnik–Fields reaction

A series of novel α-aminophosphonates of diethyl (2,4-difluorobenzylamino)methylphosphonate derivatives (4a–4g) have been synthesized by applying three-component Kabachnik–Fields reaction, using fluoro derivatives of aldehydes and substituted amines, diethyl phosphonate in the presence of a catalytic amount of methanesulfonic acid (MSA) in good yields with high enantioselectivities (up to 98% ee). The enantioselectivitiy of compounds (4a–4g) was confirmed by chiral HPLC. The direct Kabachnik–Fields reaction with high reactivity under mild reaction conditions and significantly used for synthesis of the α-aminophosphonate. The novel products were characterized by spectral and analytical data.

Efficient synthesis of α-substituted-α-arylmethyl phosphonates using trichloroacetimidate C[sbnd]C coupling method

A simple convenient protocol for the synthesis of diethyl α,α-diaryl methylphosphonate derivatives 5a-f, 6b-f, 7a-f and 8a-f, diethyl α-alkenyl α-aryl methylphosphonates 9a-d and 10a-d and α-(oxoalkyl) α-aryl methylphosphonate 11a-d and 12a-d is described. Trichloroacetimidates 3a-d were treated with activated arenes, styrene, allyltrimethylsilane or silylenol ethers C-nucleophiles in the presence TMSOTf to afford the desired products in good yields and short reaction time.

Synthesis, fluorescence properties and the promising cytotoxicity of pyrene-derived aminophosphonates.

A large series of variously substituted amino(pyren-1-yl)methylphosphonic acid derivatives was synthesized using a modified aza-Pudovik reaction in 20–97% yields. The fluorescence properties of the obtained compounds were investigated revealing that N-alkylamino(pyren-1-yl)methylphosphonic derivatives are stronger emissive compounds than the corresponding N-aryl derivatives. N-Benzylamino(pyren-1-yl)methylphosphonic acid displayed strong fluorescence (ΦF = 0.68) in phosphate-buffered saline (PBS). The influence of a series of derivatives on two colon cancer cell lines HT29 and HCT116 was also investigated. The most promising results were obtained for N-(4-methoxyphenyl)amino(pyren-1-yl)methylphosphonate, which was found to be cytotoxic for the HCT116 cancer cell line (IC50 = 20.8 μM), simultaneously showing weak toxicity towards normal lymphocytes (IC50 = 230.8 µM).

Three Component Synthesis of New (1,3,4-Thiadiazolamino)Methylphosphonates, Their Glycoside and Oxygenated Alkylthio Analogs

A number of (1,3,4-thiadiazol-2-ylamino)methylphosphonate derivatives were synthesized in a three component reaction. The thioglycoside derivatives and oxygenated alkylthio analogs were also prepared by reaction with halo sugars or different acyclic oxygenated alkyl halides.

Rapid Synthesis and Antiviral Activity of (Quinazolin-4-Ylamino)Methyl-Phosphonates Through Microwave Irradiation

This study describes the simple synthesis of new (quinazolin-4-ylamino) methylphosphonates via microwave irradiation. Substituted-2-aminobenzonitrile reacted with 1,1-dimethoxy-N,N-dimethylmethanamine at a reflux condition to obtain N′-(substituted-2-cyanophenyl)-N,N-dimethylformamidine (1). The subsequent reaction of this intermediate product with α-aminophosphonate (2) in a solution containing glacial acetic acid in 2-propanol through microwave irradiation resulted in the formation of (quinazolin-4-ylamino)methyl-phosphonate derivatives 3a to 3x, which were unequivocally characterized by the spectral data and elemental analysis. The influence of the reaction conditions on the yield of 3a was investigated to optimize the synthetic conditions. The relative optimal conditions for the synthesis of 3a include a 1:1 molar ratio of N′-(2-cyanophenyl)-N,N-dimethylformamidine to diethyl amino(phenyl)methylphosphonate and a 4:1 volume ratio of isopropanol to HOAc in the solvent mixture, at a reaction temperature of 150 °C, with a microwave power of 100 W and a corresponding pressure of 150 psi for 20 min in the microwave synthesizer. The yield of 3a was approximately 79%, whereas those of 3b to 3x were approximately 77% to 86%. Some of the synthesized compounds displayed weak to good anti-Tobacco mosaic virus (TMV) activity.

Multicomponent reactions in a one-pot synthesis of α-aminophosphonates and α-aminophosphonic diamides with anti-inflammatory properties

Schiff-base Kabachnik–Fields intermediates generated in situ from substituted pyrazole-4-carbaldehyde and 2-aminothiophene derivatives were trapped by dialkyl phosphites to produce the corresponding α-aminophosphonates in moderate yields. The latter products could be also obtained in excellent yields (≥75%) by directly applying the phosphorus reagents to the Schiff bases. Next, dialkyl phosphites were applied to one of the parent aldehydes to give the expected α-hydroxyphosphonate derivatives. Applying hexaalkyl triamidophosphites to the Schiff base in ethanol afforded methylphosphonic diamide derivatives, whereas ring attack on the pyrazole ring occurred when the same amidophosphites were applied to the parent aldehyde to give the corresponding alkylidenephosphorane ylides in an open structure form in good yields. Some of the new compounds exhibited considerable anti-inflammatory properties.

Synthesis and Evaluation of 1-Aryl-1-(7-carboxy-isoindolin-1-one-2-yl)methylphosphonic Acid Derivatives as Inhibitors of Protein Tyrosine Phosphatase

Isoindolin-1-one-2-ylmethylphosphonic acid derivatives have been synthesized as potential inhibitors of protein tyrosine phosphatases. Molecular docking calculations and assays in vitro showed that isoindolin-1-one-2-ylmethylphosphonic acid can be used as a scaffold for the design of new inhibitors of the enzymes.

Tandem Mass Spectrometry of Modified and Platinated Oligoribonucleotides

Therapeutic approaches for treatment of various diseases aim at the interruption of transcription or translation. Modified oligonucleotides, such as 2'-O-methyl- and methylphosphonate-derivatives, exhibit high resistance against cellular nucleases, thus rendering application for, e.g., antigene or antisense purposes possible. Other approaches are based on administration of cross-linking agents, such as cis-diamminedichloroplatinum(II) (cisplatin, DDP), which is still the most widely used anticancer drug worldwide. Due to the formation of 1,2-intrastrand cross links at adjacent guanines, replication of the double-strand is disturbed, thus resulting in significant cytotoxicity. Evidence for the gas-phase dissociation mechanism of platinated RNA is given, based on nano-electrospray ionization high-resolution multistage tandem mass spectrometry (MS(n)). Confirmation was found by investigating the fragmentation pattern of platinated and unplatinated 2'-methoxy oligoribonucleotide hexamers and their corresponding methylphosphonate derivatives. Platinated 2'-methoxy oligoribonucleotides exhibit a similar gas-phase dissociation behavior as the corresponding DNA and RNA sequences, with the 3'-C-O bond adjacent to the vicinal guanines being cleaved preferentially, leading to w(x)-ion formation. By examination of the corresponding platinated methylphosphonate derivatives of the 2'-methoxy oligoribonucleotides, the key role of the negatively charged phosphate oxygen atoms in direct proximity to the guanines was proven. The significant alteration of fragmentation due to platination is demonstrated by comparison of the fragment ion patterns of unplatinated and platinated 2'-O-methyl- and 2'-O-methyl methylphosphonate oligoribonucleotides, and the results obtained by H/D exchange experiments.

Synthesis and In Vitro Antimicrobial Activity of New α-Aminophosphonates via Tetrazolo [1,5-a] Quinoline Derivatives

A series of diethyl (4-fluorophenylamino) (substituted tetrazolo[1,5-a]quinolin-4-yl)methyl phosphonate derivatives has been synthesized for the first time from tetrazolo [1,5-a] quinoline derivatives. Elemental analysis, IR, 1H NMR, 13C NMR, and mass spectral data elucidated the structures of the all newly synthesized compounds. In vitro antimicrobial activities of synthesized compounds have been investigated against Gram-positive Bacillus subtilis, Gram-negative Escherichia coli, and two fungi Candida albicans and Aspergillus niger in comparison with standard drugs. Significantly, microbiological behavior of these newly synthesized derivatives possesses significant antibacterial and antifungal activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

3‘-Methylphosphonate-Modified Oligo-2‘-O-methylribonucleotides and Their Tat Peptide Conjugates: Uptake and Stability in Mouse Fibroblasts in Culture

Antisense oligo-2'-O-methylribonucleotides and their methylphosphonate derivatives show high binding affinities for their complementary targets under essentially physiological conditions. Additionally, the methylphosphonate linkage is resistant to nuclease hydrolysis. Here we show that a single methylphosphonate internucleotide linkage at the 3'-end of an oligo-2'-O-methylribonucleotide is sufficient to prevent degradation by the 3'-exonuclease activity found in mammalian serum. Complexes formed between a cationic lipid, Oligofectamine, and 5'-[(32)P]-labeled methylphosphonate modified oligo-2'-O-methylribonucleotides are taken up by mouse L(929) fibroblasts in culture. The extent of uptake appears to be dependent upon the sequence of the oligonucleotide. Examination of lysates of oligonucleotide treated cells by polyacrylamide gel electrophoresis showed that no degradation of the oligonucleotide occurred, even after incubation for 24 h. A fluorescein-derivatized oligomer was shown to localize mainly in the cell nucleus as monitored by fluorescence microscopy. Covalent conjugates of fluorescein-derivatized 3'-methylphosphonate modified oligo-2'-O-methylribonucleotides with Tat peptide, a cell permeating peptide, were also prepared. The Tat peptide was coupled to the 5'-end of the oligonucleotide using either disulfide coupling chemistry or conjugation of a keto derivative of the Tat peptide via a 4-(2-aminooxyethoxy-2-(ethylureido)quinoline group at the 5'-end of the oligonucleotide. Although formation of the Tat peptide conjugates was confirmed by mass spectrometry, the propensity of these oligonucleotides to form aggregates and their apparent high affinity for plastic and glass made the conjugates unsuitable for studies of uptake by cells in culture.

Structure and Properties of Fireproof Viscose Fibres Modified with Dimethyl Methylphosphonate

The effect of dimethyl methylphosphonate and methazine derivatives on the structural characteristics of viscose fibre is established. Chemical reaction of the fibre with the flame retardants investigated is demonstrated. The effect of flame retardants on the physicomechanical properties of the fibres is noted.

Synthesis of novel glycosyl phosphate analogues: Derivatives of an acceptor substrate for the Leishmania elongating α- d-mannopyranosylphosphate transferase

The three structural analogues of dec-9-enyl β-D-galactosyl-(1→4)-α-D-mannosyl phosphate, comprising thiophosphate, boranophosphate and methylphosphonate derivatives, were prepared via disaccharide H-phosphonate or trichloroacetimidate (for the methylphosphonate synthesis) intermediates.

Oligodeoxynucleoside phosphoramidates (P-NH2): synthesis and thermal stability of duplexes with DNA and RNA targets

Syntheses of non ionic oligodeoxynucleoside phosphoramidates (P-NH2) and mixed phosphoramidate- phosphodiester oligomers were accomplished on automated solid supported DNA synthesizer using both H-phosphonate and phosphoramidite chemistries, in combination with t-butylphenoxyacetyl for N-protection of nucleoside bases, an oxalyl anchored solid support and a final treatment with methanolic ammonia. Thermal stabilities of the hybrids formed between these new analogues and their DNA and RNA complementary strands were determined and compared with those of the corresponding unmodified oligonucleotides, as well as of the phosphorothioate and methylphosphonate derivatives. Dodecathymidines containing P-NH2 links form less stable duplexes with DNA targets, d(C2A12C2) (deltaTm/modification -1.4 degrees C) and poly dA (deltaTm/modification -1.1 degrees C) than the corresponding phosphodiester and methylphosphonate analogues, but the hybrids are slightly more stable than the one obtained with phosphorothioate derivative. The destabilization is more pronounced with poly rA as the target (deltaTm/modification -3 degrees C) and could be compared with that found with the dodecathymidine methylphosphonate. The modification is less destabilizing in an heteropolymer-RNA duplex (deltaTm/modification -2 degrees C). As expected, the P-NH2 modifications are highly resistant towards the action of various nucleases. It is also demonstrated that an all P-NH2 oligothymidine does not elicit Escherichia coli RNase H hydrolysis of the poly rA target but that the modification may be exploited in chimeric oligonucleotides combining P-NH2 sections with a central phosphodiester section.

Methylphosphonate mapping of phosphate contacts critical for RNA recognition by the human immunodeficiency virus tat and rev proteins.

The HIV-1 regulatory proteins tat and rev are both RNA binding proteins which recognize sequences in duplex RNA which are close to structural distortions. Here we identify phosphate contacts which are critical for each binding reaction by use of a new method. Model RNA binding sites are constructed carrying substitutions of individual phosphodiesters by uncharged methylphosphonate derivatives isolated separately as Rp and Sp diastereoisomers and tested for protein binding by competition assays. In the binding of tat to the trans-activation response region (TAR), three phosphates, P21 and P22 which are adjacent to the U-rich bulge and P40 on the opposite strand, are essential and in each case both isomers inhibit binding. Similarly, in the interaction between the HIV-1 rev protein and the rev-responsive element (RRE) both methylphosphonate isomers at P103, P104, P124 and P125 interfere with rev binding. At P106, only the Rp methylphosphonate isomer is impaired in rev binding ability and it is proposed that the Rp oxygen is hydrogen-bonded to an uncharged amino acid or to a main chain hydrogen atom. Synthetic chemistry techniques also provide evidence for the conformations of non-Watson-Crick G106:G129 and G105:A131 base-pairs in the RRE 'bubble' structure upon rev binding. Almost all functional groups on the 5 bulged residues in the bubble have been ruled out as sites of contact with rev but, by contrast, the N7-positions of each G residue in the flanking base-pairs are identified as sites of likely hydrogen-bonding to rev. The results show that both tat and rev recognize the major groove of distorted RNA helixes and that both proteins make specific contacts with phosphates which are displaced from the sites of base-pair contact.

Synthesis and properties of oligonucleotides containing aminodeoxythymidine units.

Procedures are described for synthesis via solid support methodology of oligonucleotide analogues derived in part from 3'-amino-3'-deoxythymidine or 5'-amino-5'-deoxythymidine. Oligothymidylate decamers terminated with a 3'-amino group or containing a 3'-NHP(O)(O-)O-5' internucleoside link are found to form unusually stable complexes with poly(dA), poly(A), and oligo(dA). For related derivatives of 5'-amino-5'-deoxythymidine enhancement is less or absent, and in the case of multiple substitution destabilization of the heteroduplex may be observed. That the effect of the 3'-amino group is general for oligonucleotide derivatives is indicated by enhanced Tm values for heteroduplex complexes of the mixed-base oligomer, d(TATTCAGTCAT(NH2)), and the methyl phosphonate derivatives, TmTmTmTmTmTmTmTmTmT(NH2) and d(TmAmTmTmCmAmGmTmCmAmT(NH2)).

Stereoselective Synthesis of Ribonucleoside 3′,5′-Cyclic Methyl(phenyl)phosphonates and Phosphonothioates

Abstract Monophosphonylation of 2′-protected ribonucleosides (i.e. 2′-O-THP-uridine and 2′-O-THP-N 6-levulinoyl-adenosine) with the bifunctional reagents bis[(6-trifluoromethyl)benzotriazol-1-yl] methyl(phenyl)phosphonates or the analogous phosphonothioates, and subsequent addition of N-methylimidazole, gave the chirally pure 3′,5′-cyclic methyl(phenyl)phosphonate or phosphonothioate derivatives, respectively. Deblocking of the fully protected compounds yielded, as evidenced by X-ray analysis, the corresponding pure Sp-diastereoisomers.

Duplex stabilities of phosphorothioate, methylphosphonate, and RNA analogs of two DNA 14-mers

The duplex stabilities of various phosphorothioate, methylphosphonate, RNA and 2'-OCH3 RNA analogs of two self-complementary DNA 14-mers are compared. Phosphorothioate and/or methylphosphonate analogs of the two sequences d(TAATTAATTAATTA) [D1] and d(TAGCTAATTAGCTA) [D2] differ in the number, position, or chirality (at the 5' terminal linkage) of the modified phosphates. Phosphorothioate derivatives of D1 are found to be less destabilized when the linkage modified is between adenines rather than between thymines. Surprisingly, no base sequence effect on duplex stabilization is observed for any methylphosphonate derivatives of D1 or D2. Highly modified phosphorothioates or methylphosphonates are less stable than their partially modified counterparts which are less stable than the unmodified parent compounds. The 'normal' (2'-OH) RNA analog of duplex D1 is slightly destabilized, whereas the 2'-OCH3 RNA derivative is significantly stabilized relative to the unmodified DNA. For the D1 sequence, at approximately physiological salt concentration, the order of duplex stability is 2'-OCH3 RNA greater than unmodified DNA greater than 'normal' RNA greater than methylphosphonate DNA greater than phosphorothioate DNA. D2 and the various D2 methylphosphonate analogs investigated all formed hairpin conformations at low salt concentrations.

ChemInform Abstract: Comparative Study of Nucleophilic and Enzymic Reactions of 2‐Propyl Methylphosphonate Derivatives

ChemInform Abstract: Comparative Study of Nucleophilic and Enzymic Reactions of 2‐Propyl Methylphosphonate Derivatives