PubMed Health⌕ Search

Biomedical subjects

Mary F Mahon

Publications and source records attributed to Mary F Mahon.

At least 19 recordsLinked to original sources
PubMed2006

Substitution and derivatization reactions of a water soluble iron(II) complex containing a self-assembled tetradentate phosphine ligand.

Facile substitution reactions of the two water ligands in the hydrophilic tetradentate phosphine complex cis-[Fe{(HOCH2)P{CH2N(CH2P(CH2OH)2)CH2}2P(CH2OH)}(H2O)2](SO4) (abbreviated to [Fe(L1)(H2O)2](SO4), 1) take place upon addition of Cl-, NCS-, N3(-), CO3(2-) and CO to give [Fe(L1)X2] (2, X = Cl; 4, X = NCS; 5, X=N3), [Fe(L1)(kappa2-O(2)CO)], 6 and [Fe(L1)(CO)2](SO4), 7. The unsymmetrical mono-substituted intermediates [Fe(L1)(H2O)(CO)](SO(4)) and [Fe(L(1))(CO)(kappa(1)-OSO(3))] (8/9) have been identified spectroscopically en-route to 7. Treatment of 1 with acetic anhydride affords the acylated derivative [Fe{(AcOCH2)P{CH2N(CH2P(CH2OAc)2)CH2}2P(CH2OAc)}(kappa2-O(2)SO2)] (abbreviated to [Fe(L2)(kappa2-O(2)SO2)], 10), which has increased solubility over 1 in both organic solvents and water. Treatment of 1 with glycine does not lead to functionalisation of L1, but substitution of the aqua ligands occurs to form [Fe(L(1))(NH(2)CH(2)CO(2)-kappa(2)N,O)](HSO(4)), 11. Compound 10 reacts with chloride to form [Fe(L(2))Cl(2)] 12, and 12 reacts with CO in the presence of NaBPh4 to form [Fe(L2)Cl(CO)](BPh4) 13b. Both of the chlorides in 12 are substituted on reaction with NCS- and N3(-) to form [Fe(L2)(NCS)2] 14 and [Fe(L2)(N3)2] 15, respectively. Complexes 2.H2O, 4.2H2O, 5.0.812H2O, 6.1.7H2O, 7.H2O, 10.1.3CH3C(O)CH3, 12 and 15.0.5H2O have all been crystallographically characterised.

Crystallography, X-Ray↗
PubMed2006

Ruthenium induced C-N bond activation of an N-heterocyclic carbene: isolation of C- and N-bound tautomers.

C-N bond activation of the N-heterocyclic carbene 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene occurs with Ru(PPh3)3(CO)HCl to give the C-2 bound 1-isopropyl-4,5-dimethylimidazol-2-ylidene complex Ru(C-IiPrHMe2)(PPh3)2(CO)HCl via loss of propene. In the presence of free carbene, this undergoes tautomerism to the corresponding imidazole compound Ru(N-IiPrHMe2)(PPh3)2(CO)HCl.

Journal Article↗
PubMed2006

Synthesis and X-ray structures of new titanium(IV) aryloxides and their exploitation for the ring opening polymerization of epsilon-caprolactone.

A series of titanium catecholates have been prepared and characterized by single-crystal X-ray diffraction studies. Complexes 1a-7a were synthesized by the reaction of 1 equiv of ligand with Ti(OiPr)4. All are dimers in the solid-state, in which a catechol bridges between two titanium centers. Electronic (nitro and methoxy groups) and steric (tert-butyl groups) effects of the ligand have been investigated. Complex 1b was synthesized by reaction of 2 equiv of ligand with Ti(OiPr)4. A dimer is again observed with the same bridging ligand together with a terminal catechol moiety. All complexes contain a coordinated 2-propanol ligand on each titanium center forming pseudo-octahedral metal centers. All complexes were tested for the ring-opening-polymerization of epsilon-caprolactone to afford polycaprolactone (PCL). Reasonable yields (up to 79%) were obtained at room temperature, and narrow molecular weight distributions (1.13-1.27) were observed for the PCL produced. The most active complex was found to be complex 1a, containing unsubsituted catechol ligands.

Journal Article↗
PubMed2006

Modification of estrone at the 6, 16, and 17 positions: novel potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.

The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyze the interconversion between the oxidized and reduced forms of androgens and estrogens at the 17 position. The 17beta-HSD type 1 enzyme (17beta-HSD1) catalyzes the reduction of estrone to estradiol and is expressed in malignant breast cells. Inhibitors of this enzyme thus have potential as treatments for hormone dependent breast cancer. Here we report the syntheses and biological evaluation of novel inhibitors based on the estrone or estradiol template. These have been investigated by modification at the 6, 16 or 17 positions or combinations of these in order to gain information about structure-activity relationships by probing different areas in the enzyme active site. Activity data have been incorporated into a QSAR with predictive power, and the X-ray crystal structures of compounds 15 and 16c have been determined. Compound 15 has an IC50 of 320 nM for 17beta-HSD1 and is selective for 17beta-HSD1 over 17beta-HSD2. Three libraries of amides are also reported that led to the identification of inhibitors 19e and 20a, which have IC50 values of 510 and 380 nM respectively, and 20 h which, having an IC50 value of 37 nM, is the most potent inhibitor of 17beta-HSD1 reported to date. These amides are also selective for 17beta-HSD1 over 17beta-HSD2.

17-Hydroxysteroid Dehydrogenases↗
PubMed2006

Structure and reactivity of new phosphine ligands containing the hemi-labile sulfone moiety.

New heterofunctional phosphine ligands have been synthesised, incorporating the substitutionally labile sulfone and sulfonamide moieties as chelating groups, which display activity in the palladium-catalysed Suzuki and amination cross-coupling reactions. Single-crystal X-ray diffraction studies of the complexes formed with [Pd(mu-Cl)(dmba)] (dmba-H = N,N-dimethylbenzylamine) highlight the coordinating nature of these ligands; showing the formation of a bis chelate complex through a six-membered Pd-P-C-C-S-O ring with the sulfonamide class of ligands.

Journal Article↗
PubMed2006

Focused libraries of 16-substituted estrone derivatives and modified e-ring steroids: inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.

17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone-dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16-substituted estrone derivatives and modified E-ring pyrazole steroids as new potent 17beta-HSD1 inhibitors is described. Substituted 3-O-sulfamoylated estrone derivatives were used as templates and were immobilised on 2-chlorotrityl chloride resin to give resin-bound scaffolds with a multi-detachable linker. Novel focused libraries of 16-substituted estrone derivatives and new modified E-ring steroids were assembled from these immobilised templates using solid-phase organic synthesis and solution-phase methodologies. Among the derivatives synthesised, the most potent 17beta-HSD1 inhibitors were 25 and 26 with IC50 values in T-47D human breast cancer cells of 27 and 165 nm, respectively. Parallel synthesis resulting in a library of C5'-linked amides from the pyrazole E-ring led to the identification of 62 with an IC50 value of 700 nM. These potent inhibitors of 17beta-HSD1 have a 2-ethyl substituent which will decrease their estrogenic potential. Several novel 17beta-HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X-ray crystal structure of this inhibitor is presented.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

E-ring modified steroids as novel potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are an important class of steroidogenic enzymes that regulate the bioavailability of active estrogens and androgens and are as yet a relatively unexploited therapeutic target. Based on our investigations and those of others, E-ring modified steroids were identified as a useful template for the design of inhibitors of 17beta-HSD type 1, an enzyme involved in the conversion of estrone into estradiol. The synthesis and biological evaluation of a new series of N- and C-substituted 1,3,5(10)-estratrien-[17,16-c]-pyrazoles and the corresponding SAR are discussed. Among the N-alkylated analogues, the most potent inhibitor was the 1'-methoxyethyl derivative, 41, with an IC(50) of 530 nM in T47-D human breast cancer cells. The X-ray crystal structure of the 1'-isobutyl derivative, was determined. Further optimization of the template using parallel synthesis resulted in a library of C5'-linked amides from which 73 emerged. This pyridylethyl amide had an IC(50) of 300 nM and its activity, with that of 41, suggests the importance of hydrogen bond acceptor groups in the pyrazole side chain. Both 41 and 73 displayed selectivity over 17beta-HSD type 2, and preliminary investigations showed 41 to be nonestrogenic in vitro in a luciferase reporter gene assay in contrast to the parent pyrazole 25. Molecular modeling studies, which support these findings, and a QSAR, the predictive power of which was demonstrated, are also presented.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

A-ring-substituted estrogen-3-O-sulfamates: potent multitargeted anticancer agents.

Efficient and flexible syntheses of 2-substituted estrone, estradiol and their 3-O-sulfamate (EMATE) derivatives have been developed using directed ortho-lithiation methodology. 2-Substituted EMATEs display a similar antiproliferative activity profile to the corresponding estradiols against a range of human cancer cell lines. 2-Methoxy (3, 4), 2-methylsulfanyl (20, 21) and 2-ethyl EMATEs (32, 33) proved the most active compounds with 2-ethylestradiol-3-O-sulfamate (33), displaying a mean activity over the NCI 55 cell line panel 80-fold greater than the established anticancer agent 2-methoxyestradiol (2). 2-Ethylestradiol-3-O-sulfamate (33) was also an effective inhibitor of angiogenesis using three in vitro markers, and various 2-substituted EMATEs also proved to be inhibitors of steroid sulfatase (STS), a therapeutic target for the treatment of hormone-dependent breast cancer. The potential of this novel class of multimechanism anticancer agents was confirmed in vivo with good activity observed in the NCI hollow fiber assay and in a MDA-MB-435 xenograft mouse model.

Angiogenesis Inhibitors↗
PubMed2005

Stereoselective synthesis of (E)-trisubstituted alpha,beta-unsaturated amides and acids.

Potassium alkoxides of N-acyl-oxazolidin-2-one-syn-aldols undergo stereoselective elimination reactions to afford a range of trisubstituted (E)-alpha,beta-unsaturated amides in >95% de, that may be subsequently converted into their corresponding (E)-alpha,beta-unsaturated acids or (E)-alpha,beta-unsaturated oxazolines in good yield. syn-Aldols derived from alpha,beta-unsaturated aldehydes gave their corresponding trisubstituted (E)-alpha,beta-unsaturated-amides with poorer levels of diastereocontrol, whilst there was a similar loss in (E)-selectivity during elimination of syn-aldols derived from chiral aldehydes. These elimination reactions proceed via rearrangement of the potassium alkoxide of the syn-aldol to a 1,3-oxazinane-2,4-dione enolate intermediate that subsequently eliminates carbon dioxide to afford a trisubstituted (E)-alpha,beta-unsaturated amide. The (E)-selectivity observed during the E1cB-type elimination step has been rationalised using a simple conformational model that employs a chair-like transition state to explain the observed stereocontrol.

Amides↗
PubMed2005

Dihydrogen complexes of rhodium: [RhH2(H2)x (PR3)2]+ (R = Cy, iPr; x = 1, 2).

Addition of H2 (4 atm at 298 K) to [Rh(nbd)(PR3)2][BAr(F)4] [R = Cy, iPr] affords Rh(III) dihydride/dihydrogen complexes. For R = Cy, complex 1a results, which has been shown by low-temperature NMR experiments to be the bis-dihydrogen/bis-hydride complex [Rh(H)2(eta2-H2)2(PCy3)2][BAr(F)4]. An X-ray diffraction study on 1a confirmed the {Rh(PCy3)2} core structure, but due to a poor data set, the hydrogen ligands were not located. DFT calculations at the B3LYP/DZVP level support the formulation as a Rh(III) dihydride/dihydrogen complex with cis hydride ligands. For R = iPr, the equivalent species, [Rh(H)2(eta2-H2)2(P iPr3)2][BAr(F)4] 2a, is formed, along with another complex that was spectroscopically identified as the mono-dihydrogen, bis-hydride solvent complex [Rh(H)2(eta2-H2)(CD2Cl2)(P iPr3)2][BAr(F)4] 2b. The analogous complex with PCy3 ligands, [Rh(H)2(eta2-H2)(CD2Cl2)(PCy3)2][BAr(F)4] 1b, can be observed by reducing the H2 pressure to 2 atm (at 298 K). Under vacuum, the dihydrogen ligands are lost in these complexes to form the spectroscopically characterized species, tentatively identified as the bis hydrides [Rh(H)2(L)2(PR3)2][BAr(F)4] (1c R = Cy; 2c R = iPr; L = CD2Cl2 or agostic interaction). Exposure of 1c or 2c to a H2 atmosphere regenerates the dihydrogen/bis-hydride complexes, while adding acetonitrile affords the bis-hydride MeCN adduct complexes [Rh(H)2(NCMe)2(PR3)2][BAr(F)4]. The dihydrogen complexes lose [HPR3][BAr(F)4] at or just above ambient temperature, suggested to be by heterolytic splitting of coordinated H2, to ultimately afford the dicationic cluster compounds of the type [Rh6(PR3)6(mu-H)12][BAr(F)4]2 in moderate yield.

Journal Article↗
PubMed2005

Novel and potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors.

Structure-based drug design using the crystal structure of human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) led to the discovery of novel, selective, and the most potent inhibitors of 17beta-HSD1 reported to date. Compounds 1 and 2 contain a side chain with an m-pyridylmethyl-amide functionality extended from the 16beta position of a steroid scaffold. A mode of binding is proposed for these inhibitors, and 2 is a steroid-based 17beta-HSD1 inhibitor with the potential for further development.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Mononuclear and dinuclear complexes with a [Ru(tBu2PCH2CH2PtBu2)(CO)] core.

Thermolysis of solid [Ru(d(t)bpe)(CO)2Cl2](2, d(t)bpe =(t)Bu2PCH2CH2P(t)Bu2) under vacuum affords the five-coordinate complex [Ru(d(t)bpe)(CO)Cl2] (4), which was shown by X-ray crystallography to contain a weak remote agostic interaction. In solution, 4 can be readily trapped by CO, CH3CN or water to give [Ru(d(t)bpe)(CO)(L)Cl2](L = CO, 2; L = CH3CN, 6; L = H2O, 7). Reaction of 4 with AgOTf/H2O yields the tris-aqua complex [Ru(d(t)bpe)(CO)(H2O)3](OTf)2 (8), which has been structurally characterised and probed in solution by pulsed-gradient spin echo (PGSE) NMR spectroscopy. The water ligands in 8 are labile and easily substituted to give [Ru(d(t)bpe)(CO)(NCCH3)3](OTf)2 (10) and [Ru(d(t)bpe)(CO)(DMSO)3](OTf)2 (11). In the presence of CO, the tris-aqua complex undergoes water-gas shift chemistry with formation of the cationic hydride species [Ru(d(t)bpe)(CO)3H](OTf) (12) and CO2. X-Ray crystal structures of complexes 2, 4, 6, 8 and 11-12 are reported along with those for [{Ru(d(t)bpe)(CO)}2(mu-Cl)2(mu-OTf)](OTf) (3), [{Ru(d(t)bpe)(CO)}2(mu-Cl)3][Ru(d(t)bpe)(CO)Cl3](5) and [Ru(d(t)bpe)(CO)(H2O)2(OTf)](OTf)(9).

Journal Article↗
PubMed2004

An enantioselective fluorescent sensor for sugar acids.

Chiral fluorescent boronic acid 1 was found to be a highly enantioselective, chemoselective, and sensitive sensor for sugar acids, such as tartaric acid. Enantioselectivities (K(R)/K(S)) of up to 550:1, chemoselectivity up to 11,000:1, and sensitivities in the micromolar range with sensor 1 were observed. Single-crystal X-ray analysis was used to confirm the structure of the fluorescent species.

Boronic Acids↗
PubMed2004

Tin(IV) halide complexes of AsPh3) The structures of trans-SnCl4(AsPh3)2 and SnBr4(AsPh3).AsPh3.

The structures of two 1 : 2 adducts between tin(IV) halides and AsPh(3) have been determined. SnCl(4)(AsPh(3))(2) adopts a six-coordinate geometry at tin in which the two organoarsine donors are mutually trans. In contrast, SnBr(4)(AsPh(3))(2) is five-coordinate at tin and only one arsine is directly bonded to the metal, in an axial site of the trigonal bipyramid. The second AsPh(3) group has a close contact with the axially bound bromine [As...Br: 3.567(3) angstroms], which is a unique structural variation that depicts an intermediate in a halogen-transfer reaction between Group 14 and Group 15 elements. AACVD using SnCl(4)(AsPh(3))(2) generates a film containing SnO(2) and a second crystalline material which is possibly SnCl(2), but which contains no arsenic.

Journal Article↗
PubMed2004

Transition metal complexes of the chelating phosphine borane ligand Ph2PCH2Ph2P.BH3.

Chromium and ruthenium complexes of the chelating phosphine borane H(3)B.dppm are reported. Addition of H(3)B.dppm to [Cr(CO)(4)(nbd)](nbd = norbornadiene) affords [Cr(CO)(4)(eta1-H(3)B.dppm)] in which the borane is linked to the metal through a single B-H-Cr interaction. Addition of H(3)B.dppm to [CpRu(PR(3))(NCMe)(2)](+)(Cp =eta5)-C(5)H(5)) results in [CpRu(PR(3))(eta1-H(3)B.dppm)][PF(6)](R = Me, OMe) which also show a single B-H-Ru interaction. Reaction with [CpRu(NCMe)(3)](+) only resulted in a mixture of products. In contrast, with [Cp*Ru(NCMe)(3)](+)(Cp*=eta5)-C(5)Me(5)) a single product is isolated in high yield: [Cp*Ru(eta2-H(3)B.dppm)][PF(6)]. This complex shows two B-H-Ru interactions. Reaction with L = PMe(3) or CO breaks one of these and the complexes [Cp*Ru(L)(eta1-H(3)B.dppm)][PF(6)] are formed in good yield. With L = MeCN an equilibrium is established between [Cp*Ru(eta2-H(3)B.dppm)][PF(6)] and the acetonitrile adduct. [Cp*Ru (eta2-H(3)B.dppm)][PF(6)] can be considered as being "operationally unsaturated", effectively acting as a source of 16-electron [Cp*Ru (eta1-H(3)B.dppm)][PF(6)]. All the new compounds (apart from the CO and MeCN adducts) have been characterised by X-ray crystallography. The solid-state structure of H(3)B.dppm is also reported.

Journal Article↗
PubMed2004

Sterically hindered electron-withdrawing ligands: the reactions of N-carbazolyl phosphines with rhodium and palladium centres.

The series of N-carbazolyl phosphines PPh(3-n)(NC(12)H(8))(n)(n= 1, L1; n= 2, L2; n= 3, L3) has been synthesised using BuLi to generate the N-carbazolyl lithium salt, followed by reaction with the appropriate chlorophosphine. The reactions between [Rh(mu-Cl)(CO)(2)](2) and four equivalents of L1 or L2 gave [RhCl(CO)(L1)(2)] 1 and [RhCl(CO)(L2)(2)] 2, though attempts to synthesise the analogous complex using L3 resulted in the formation of [Rh(mu-Cl)(CO)(L3)](2) 3 instead. The inability of L3 to cleave the chloride bridges can be related to its considerable steric requirements. The electronic properties of L1-3 were assessed by comparison of the nu(CO) values of the [Rh(acac)(CO)(L1-3)] complexes 4-6. The increase in number of N-carbazolyl substituents at the phosphorus atom results in a decrease of the sigma-donor and increase in the pi-acceptor character in the order L1 < L2 < L3. In the reactions of L1-3 with [PdCl(2)(cod)] only L1 was able to displace cod from the metal centre and form [PdCl(2)(L1)(2)] 7. The use of [PdCl(2)(NCMe)(2)] instead of [PdCl(2)(cod)] resulted in the formation of the complexes [PdCl(2)(L1)(2)] 7 from L1, the cyclometallated complex [Pd(mu-Cl)[P(NC(12)H(8))(2)(NC(12)H(7))-kappa(2)P,C]](2) 8 from L3 , and a mixture of [PdCl(2)(L2)(2)] 9 and [Pd(mu-Cl)[PPh(NC(12)H(8))(NC(12)H(7))-kappa(2)P,C]](2) 10 from L2 . The reaction of L3 with [Pd(OAc)(2)] produced the cyclometallated complex [Pd(mu-O(2)CCH(3))[P(NC(12)H(8))(2)(NC(12)H(7))-kappa(2)P,C]](2) 11. The reaction of L3 with [Pd(2)(dba)(3)].CHCl(3) produced the 14-electron complex [Pd(L3)(2)] 12. The X-ray crystal structures of six complexes are reported, all of which show the presence of C-H...Pd hydrogen bonding.

Journal Article↗