Ving Lee - Academia.edu (original) (raw)
Papers by Ving Lee
Journal of Medicinal Chemistry, Jul 1, 1993
The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodru... more The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was injected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and antitumor activity. While the antitumor activities of 6 in mice were comparable to bisantrene against B-16 melanoma and P-388 and L-1210 leukemias, it was inactive in vitro vs several tumor cell types. Thus, its activity in vivo resulted from its ability to serve as a prodrug for bisantrene.
Ethyl 1-Naphthylacetate reactant: 30.5 g. (0.160 mole) of 1-naphthoyl chloride intermediate: 1-(d... more Ethyl 1-Naphthylacetate reactant: 30.5 g. (0.160 mole) of 1-naphthoyl chloride intermediate: 1-(diazoacetyl)naphthalene product: ethyl 1-naphthylacetate reactant: 1-naphthoic acid reactant: 1-bromonaphthalene solvent: propyl 1-naphthylacetate Keywords: diazotization, preparation of diazonium salts; esterification, of substituted monobasic acids; rearrangements; assay methods, for diazomethane; diethyl ether; 1-naphthoyl chloride, preparation of; silver benzoate, preparation of; 1-(diazoacetyl)naphthalene, skin irritant; diazomethane, explosive, toxic
Journal of Organic Chemistry, Feb 1, 1975
Elsevier eBooks, 1991
The 1,4-conjugate addition of stabilized carbanions (1,3-dicarbonyl class) to α,β-unsaturated car... more The 1,4-conjugate addition of stabilized carbanions (1,3-dicarbonyl class) to α,β-unsaturated carbonyl compounds was reported by Michael in 1887 and quickly became established as an efficient method for carboncarbon bond formation.1 Numerous stabilized nucleophiles (donors) have been found to participate efficiently in 1,4-conjugate additions to other activated alkenes (acceptors).2 In general, the reactivity of acceptors (a3-synthons) towards various stabilized carbanions follows: α,β-unsaturated aldehydes >> α,β-unsaturated ketones > α,β-unsaturated nitriles > α,β-unsaturated esters > α,β-unsaturated amides.3 Although the basic synthetic principles and reactivity were investigated in early years, limitations to this versatile form of carboncarbon bond formation were observed. For example, the addition of organolithiums or organomagnesium halides to α,β-unsaturated aldehydes affords exclusive 1,2addition, while additions to α,β-unsaturated ketones afford predominant 1,2-addition. During the last four decades intensive research in the use of unstabilized carbon nucleophiles for 1,4-conjugate additions was stimulated by three events. First, Kharasch and Tawney reported that preferential 1,4-conjugate addition of alkylmagnesium halides to isophorone was effected by catalytic amounts of copper(I) chloride,4 and second, House, Respess and Whitesides showed that the actual reactive species in the earlier work was an organocopper species.5 Third, Gilman and Kirby reported a comparative study of the addition of various aryl metallics to benzalacetophenone (1,3-diphenylpropene-1-one) in which several Group II (R2Cd and R2Zn) and Group III (R3Al) organometallics afforded exclusive 1,4-conjugate addition.6
Expert Opinion on Therapeutic Patents, Mar 1, 1999
The intellectual property literature in β-lactam antibacterial research for the period of 1995-19... more The intellectual property literature in β-lactam antibacterial research for the period of 1995-1998 is reviewed. The majority of the citations described herein involves the synthesis and evaluation of new compounds.
![Research paper thumbnail of The synthesis of 1-[(2-thiazolyl)methyl]quinolones. The reactivity of the methylene bridge at position-1 and its involvement in the formation of a stable carbon-nitrogen ylid](https://attachments.academia-assets.com/115865063/thumbnails/1.jpg)
](Journal of Heterocyclic Chemistry, 1988
Journal of Organic Chemistry, Jul 1, 1973
On treatment of 3-nitroso-4-methyl-5,5-pentamethylene-2-oxazolidone (3) with sodium 2-methoxyetho... more On treatment of 3-nitroso-4-methyl-5,5-pentamethylene-2-oxazolidone (3) with sodium 2-methoxyethoxide in 2-methoxyethanol, or with sodium methoxide in methanol,-15-20% yields of 1,l-pentamethyleneallene (4) are obtained, together with several other compounds. Similarly, 3-nitroso-4,5,5-trimethyl-2-oxazolidone (1 1) yields 6-701, 1,l-dimethylallene (13), and 3-nitroso-l,5-dimethyl-5-tert-b~~tyl-2-oxazolidone (12) yields l-methyl-1-tert-butylallene (14) in 15% yield. The reaction of pinacolone with zinc and methyl a-bromopropionate yields the expected mixture of diastereoisomers of methyl 3-hydroxy-2,3,4,4-tetramethylpentanoate (IS), if carried out under mild conditions. Long refluxing, however, results in the formation of a,p,p,y-tetramethylvalerolactone (16). Studies of the reactions which occur when 3-nitroso-5,5-dialkyl-2-oxazolidones (1) are treated with bases CHZNNO RZCHNNO 1 2 have proved of interest not only because of the wide variety of products produced but also because of the multiplicity of mechanistic interpretations used to account for the result^.^ The present study on the reactions of 3-nitroso-4,5,5-trialky1-2-oxazolidones (2) waa undertaken for three main reasons: (1) to find out the synthetic utility of such reactions, (2) to learn more about the behavior of unsaturated cations, and (3) to compare the products formed from diastereoisomers of type 2. The most detailed study of reaction products was carried out with 3-nitroso-4-methyl-5,5-pentamethylene-2-oxazolidone (3) when treated with sodium 2methoxyethoxide in 2-methoxyethanol. The main products were 1,1-~entamethyleneallene~ (4), 1-(2methoxyethoxy)ethylidenecyclohexane (6), and 1-[l-(2-met hox y et hox y) ethyl ]cy clo hexyl 2-me t hox ye t hyl carbonate (8) I Smaller amounts of l-vinylcyclohex-(1) This work was supported in part by Grant 12445X of the National Saience Foundation. (2) This work was done in an undergraduate research program by Mr.
Journal of Organic Chemistry, Sep 1, 1993
Elsevier eBooks, 1998
... LOADING... SECTION 111. CANCER AND INFECTIOUS DISEASES Editor: Jacob J. Plattner Chiron Corpo... more ... LOADING... SECTION 111. CANCER AND INFECTIOUS DISEASES Editor: Jacob J. Plattner Chiron Corporation, Emeryville, CA 94608 Chapter 12. ... Agents Chemother., 1 (1995). AF Cowman and S. Karcz, Cell Bio., 4 2 9 (1993). KE Brighty in "Ann. Rep. Med. ...
Elsevier eBooks, 1991
The conjugate addition of stabilized carbanions, nonstabilized carbanions and heteroanions to act... more The conjugate addition of stabilized carbanions, nonstabilized carbanions and heteroanions to activated alkenes and alkynes has been discussed extensively in previous chapters in this volume (Chapters 1.1 and 1.2). In summary, the regioselectivity of carbanion additions is sensitive to: (i) the electronegativity of the metal center;1 (ii) the Hard and Soft Acid–Base (HSAB) characteristics of the metal center and the transferring ligand;2 (iii) the structure of the acceptor;3 and (iv) reaction conditions and solvent effects.4 The difference in electronegativity between a metal and carbon is reflected in the degree of ionic character imparted to the carbon–metal σ-bond and the direction of polarization.5 Thus the highly ionic Groups IA and IIA organometallics (RK, RNa, RLi and RMgX; Volume 4, Chapter 1.2) are extremely reactive, in contrast to the less ionic Group IIB organometallics (R2Cd and R2Zn; Volume 4, Chapter 1.2).
Journal of Organic Chemistry, Jul 1, 1979
Unnatural Cyclic Amino Acids was crystallized from n-hexane and then recrystallized from n-hexane... more Unnatural Cyclic Amino Acids was crystallized from n-hexane and then recrystallized from n-hexane-ethyl acetate to give the heptatriene 5 (50 mg, 50%); mp 166-167 "C. Concentration of the filtrate gave starting 7 (40 mg, 40%), mp 174-175 "C, from n-hexane. Both compounds gave satisfactory mixture melting points. X-Ray S t r u c t u r e of' Photoproduct B. Colorless crystals of tricyclophotoproduct 7 !were grown from a hexane solution. The crystal selected for structure analysis was a parallelepiped with approximate dimensions 0.30 X 0.23 X 0.23 mm and was mounted on a glass fiber with silicone adhesive. Precession photographs of this crystal led to a space group assignment of P2Jc with lattice constants of a = 1.4.813 (2) A, b = 10.717 (2) A, c = 16.827 (3) A, and p = 80.84 (21". The observed and calculated densities, assuming four molecules, of CS7Hm per unit cell volume, were 1.18 Data were collected on a Picker FACS 1 diffractometer by using the 0-28 scan technique with Zr-filtered Mo K a radiation and a takeoff angle of ,-2.5". Each of the 3774 independent data (28 5 45.77") was scanned 1.2" in 20 plus an allowance for spectral dispersion at a rate of l"/min, and backgrounds were of 20-s duration. Three standards inserted after every 100 reflections remained statistically constant. The data were reduced to a set of IF,l's by application of Lorentz and polarization corrections (L p). Standard deviations were calculated according to g/mL. OF = [(C' + k2B)/41F,1z(Lp)z]1/2 where C and B are the counts of scan and backgrounds, respectively, and k is the riitio of scan to background counting time. Some 2897 data with F, > 2aF were taken as observed and used in final stages of refinement. Normalized structure factor amplitudes [El's were calculated16 and the largest 400 were used in the reiterative application of the Sayre equati011.l~ Carbo11 atomic positions found from an E map1* were used in full-matrix isotropic refinement19,z@ followed by-(16) Program FAME by €1. Dewar and A. Stone was used. (17) Program REL by R. E. Long was used. (18) Program FORDAP by A. Zalkin was used.
Journal of the American Chemical Society, Jun 1, 1978
BENTHAM SCIENCE PUBLISHERS eBooks, Mar 26, 2012
Active efflux is a widespread mechanism for bacterial resistance to antibiotics, which contribute... more Active efflux is a widespread mechanism for bacterial resistance to antibiotics, which contributes to poor intrinsic susceptibility, cross-resistance to structurally diverse classes of drugs, or selection of other mechanisms of resistance. Thus, inhibition of efflux pumps appears to be (i) a promising strategy for restoring the activity of existing antibiotics, and (ii) a useful method to detect the presence of efflux determinants in clinical isolates. Structurally dissimilar classes of inhibitors have been patented in the last decade, some are analogs of antibiotic substrates [tetracyclines, quinolones or aminoglycosides] and others, new chemical entities [including substituted indoles, ureas, aromatic amides, piperidinecarboxylic acids, alkylamino-or alkoxyquinolines, peptidomimetics, and pyridopyrimidines]. Their spectrum of activity, in terms of antibiotics and bacteria, differ significantly. Narrow spectrum inhibitors are of prime interest as diagnostic tools, while broad spectrum inhibitors are expected for adjuvant therapies. Apart from (i) a peptidomimetic inhibitor of Mex pumps in Pseudomonas aeruginosa (MC-04,124), for which efficacy was evaluated in animal models, and (ii) a piperidinecarboxylic acid inhibitor of fluoroquinolone efflux in Gram-positive (VX-710), which was safely administered to humans, most of these products have only demonstrated their activity in vitro, so further investigations are needed to evaluate their clinical potential.
Journal of Medicinal Chemistry, Jul 1, 1991
Tazobactam (3, Cl&,,N40,S) is an effective inhibitor of bacterial 6-lactamases. It crystallizes w... more Tazobactam (3, Cl&,,N40,S) is an effective inhibitor of bacterial 6-lactamases. It crystallizes with unit cell dimensions a = 10.230 (2) A, b = 14.396 (2) A, and c = 17.291 (2) 8, in space group P2,2121. Compared to the related inhibitor sulbactam (2), which lacks the triazole ring, crystalline tazobactam exhibits very similar P-lactam geometry and the same S(1) envelope conformation of the thiazolidine ring. However, in both independent molecules of 3 a triazole ring nitrogen atom accepts an intermolecular hydrogen bond; similar interaction by this moiety of 3 with a hydrogen-bond donor on the enzyme, which is impossible for 2, could account for its enhanced inhibitory power. Semiempirical molecular orbital calculations show pronounced negative potential there. Molecular mechanics supports the hypothesis that the carboxyl group can rotate freely and the triazole ring can "flip".
Medicinal Research Reviews, Nov 1, 1999
Two discovery approaches directed to addressing the problem of increasing bacterial resistance ar... more Two discovery approaches directed to addressing the problem of increasing bacterial resistance are described. The first is a program to build activity against methicillin-resistant Staphylococcus aureus (MRSA) into the cephalosporin class of antibacterials, by enhancing affinity for PBP2a, the penicillin-binding protein responsible for this resistance. Through stepwise improvement in potency, human serum binding, solubility, and betalactamase stability, a stable of new compounds with excellent potential as anti-MRSA agents was realized. From this set was chosen MC-02, 479 (RWJ-54428), which is now undergoing extensive preclinical evaluation. The second approach explores the uridyl peptide family of antibiotics, inhibitors of bacterial translocase (mraY), whose members include the pacidamycins, mureidomycins, and napsamycins. Access to a diverse set of analogs by total synthesis was catalyzed by the discovery that hydrogenation of the 4'-exoenamidofuranosyl moiety causes no loss in biological activity. Indepth exploration of SAR required (1) establishment of the absolute stereochemistry of the central diaminobutyric acid (DABA) moiety and (2) determination of the stereochemistry of the 4'-substituent on the deoxyfuranose unit. The former was accomplished by comparison of DABA derived from degradation of a natural product pacidamycin with a sample synthesized from L-threonine. The biological activity of one member of a synthesized library of possible stereoisomers of the natural product established the absolute stereochemistry of the remaining centers. A variety of analogs of the natural product were prepared utilizing the synthetic methods developed, and their biological activities provide important insights into the specificity and spectrum of the antibiotic class.
ChemInform, Jul 14, 2010
ABSTRACT
Expert Opinion on Therapeutic Patents, Aug 1, 1995
The patent status of tetracycline research for the period of 1991 to 1995 is presented. Topics co... more The patent status of tetracycline research for the period of 1991 to 1995 is presented. Topics covered include new tetracyclines with intrinsic antibacterial activity against tetracycline-resistant bacteria or which potentiate the activity of the older tetracyclines, new natural products, new chemical methods, and non-infectious disease uses for tetracyclines.
Journal of Medicinal Chemistry, Jul 1, 1993
The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodru... more The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was injected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and antitumor activity. While the antitumor activities of 6 in mice were comparable to bisantrene against B-16 melanoma and P-388 and L-1210 leukemias, it was inactive in vitro vs several tumor cell types. Thus, its activity in vivo resulted from its ability to serve as a prodrug for bisantrene.
Ethyl 1-Naphthylacetate reactant: 30.5 g. (0.160 mole) of 1-naphthoyl chloride intermediate: 1-(d... more Ethyl 1-Naphthylacetate reactant: 30.5 g. (0.160 mole) of 1-naphthoyl chloride intermediate: 1-(diazoacetyl)naphthalene product: ethyl 1-naphthylacetate reactant: 1-naphthoic acid reactant: 1-bromonaphthalene solvent: propyl 1-naphthylacetate Keywords: diazotization, preparation of diazonium salts; esterification, of substituted monobasic acids; rearrangements; assay methods, for diazomethane; diethyl ether; 1-naphthoyl chloride, preparation of; silver benzoate, preparation of; 1-(diazoacetyl)naphthalene, skin irritant; diazomethane, explosive, toxic
Journal of Organic Chemistry, Feb 1, 1975
Elsevier eBooks, 1991
The 1,4-conjugate addition of stabilized carbanions (1,3-dicarbonyl class) to α,β-unsaturated car... more The 1,4-conjugate addition of stabilized carbanions (1,3-dicarbonyl class) to α,β-unsaturated carbonyl compounds was reported by Michael in 1887 and quickly became established as an efficient method for carboncarbon bond formation.1 Numerous stabilized nucleophiles (donors) have been found to participate efficiently in 1,4-conjugate additions to other activated alkenes (acceptors).2 In general, the reactivity of acceptors (a3-synthons) towards various stabilized carbanions follows: α,β-unsaturated aldehydes >> α,β-unsaturated ketones > α,β-unsaturated nitriles > α,β-unsaturated esters > α,β-unsaturated amides.3 Although the basic synthetic principles and reactivity were investigated in early years, limitations to this versatile form of carboncarbon bond formation were observed. For example, the addition of organolithiums or organomagnesium halides to α,β-unsaturated aldehydes affords exclusive 1,2addition, while additions to α,β-unsaturated ketones afford predominant 1,2-addition. During the last four decades intensive research in the use of unstabilized carbon nucleophiles for 1,4-conjugate additions was stimulated by three events. First, Kharasch and Tawney reported that preferential 1,4-conjugate addition of alkylmagnesium halides to isophorone was effected by catalytic amounts of copper(I) chloride,4 and second, House, Respess and Whitesides showed that the actual reactive species in the earlier work was an organocopper species.5 Third, Gilman and Kirby reported a comparative study of the addition of various aryl metallics to benzalacetophenone (1,3-diphenylpropene-1-one) in which several Group II (R2Cd and R2Zn) and Group III (R3Al) organometallics afforded exclusive 1,4-conjugate addition.6
Expert Opinion on Therapeutic Patents, Mar 1, 1999
The intellectual property literature in β-lactam antibacterial research for the period of 1995-19... more The intellectual property literature in β-lactam antibacterial research for the period of 1995-1998 is reviewed. The majority of the citations described herein involves the synthesis and evaluation of new compounds.
Journal of Heterocyclic Chemistry, 1988
Journal of Organic Chemistry, Jul 1, 1973
On treatment of 3-nitroso-4-methyl-5,5-pentamethylene-2-oxazolidone (3) with sodium 2-methoxyetho... more On treatment of 3-nitroso-4-methyl-5,5-pentamethylene-2-oxazolidone (3) with sodium 2-methoxyethoxide in 2-methoxyethanol, or with sodium methoxide in methanol,-15-20% yields of 1,l-pentamethyleneallene (4) are obtained, together with several other compounds. Similarly, 3-nitroso-4,5,5-trimethyl-2-oxazolidone (1 1) yields 6-701, 1,l-dimethylallene (13), and 3-nitroso-l,5-dimethyl-5-tert-b~~tyl-2-oxazolidone (12) yields l-methyl-1-tert-butylallene (14) in 15% yield. The reaction of pinacolone with zinc and methyl a-bromopropionate yields the expected mixture of diastereoisomers of methyl 3-hydroxy-2,3,4,4-tetramethylpentanoate (IS), if carried out under mild conditions. Long refluxing, however, results in the formation of a,p,p,y-tetramethylvalerolactone (16). Studies of the reactions which occur when 3-nitroso-5,5-dialkyl-2-oxazolidones (1) are treated with bases CHZNNO RZCHNNO 1 2 have proved of interest not only because of the wide variety of products produced but also because of the multiplicity of mechanistic interpretations used to account for the result^.^ The present study on the reactions of 3-nitroso-4,5,5-trialky1-2-oxazolidones (2) waa undertaken for three main reasons: (1) to find out the synthetic utility of such reactions, (2) to learn more about the behavior of unsaturated cations, and (3) to compare the products formed from diastereoisomers of type 2. The most detailed study of reaction products was carried out with 3-nitroso-4-methyl-5,5-pentamethylene-2-oxazolidone (3) when treated with sodium 2methoxyethoxide in 2-methoxyethanol. The main products were 1,1-~entamethyleneallene~ (4), 1-(2methoxyethoxy)ethylidenecyclohexane (6), and 1-[l-(2-met hox y et hox y) ethyl ]cy clo hexyl 2-me t hox ye t hyl carbonate (8) I Smaller amounts of l-vinylcyclohex-(1) This work was supported in part by Grant 12445X of the National Saience Foundation. (2) This work was done in an undergraduate research program by Mr.
Journal of Organic Chemistry, Sep 1, 1993
Elsevier eBooks, 1998
... LOADING... SECTION 111. CANCER AND INFECTIOUS DISEASES Editor: Jacob J. Plattner Chiron Corpo... more ... LOADING... SECTION 111. CANCER AND INFECTIOUS DISEASES Editor: Jacob J. Plattner Chiron Corporation, Emeryville, CA 94608 Chapter 12. ... Agents Chemother., 1 (1995). AF Cowman and S. Karcz, Cell Bio., 4 2 9 (1993). KE Brighty in "Ann. Rep. Med. ...
Elsevier eBooks, 1991
The conjugate addition of stabilized carbanions, nonstabilized carbanions and heteroanions to act... more The conjugate addition of stabilized carbanions, nonstabilized carbanions and heteroanions to activated alkenes and alkynes has been discussed extensively in previous chapters in this volume (Chapters 1.1 and 1.2). In summary, the regioselectivity of carbanion additions is sensitive to: (i) the electronegativity of the metal center;1 (ii) the Hard and Soft Acid–Base (HSAB) characteristics of the metal center and the transferring ligand;2 (iii) the structure of the acceptor;3 and (iv) reaction conditions and solvent effects.4 The difference in electronegativity between a metal and carbon is reflected in the degree of ionic character imparted to the carbon–metal σ-bond and the direction of polarization.5 Thus the highly ionic Groups IA and IIA organometallics (RK, RNa, RLi and RMgX; Volume 4, Chapter 1.2) are extremely reactive, in contrast to the less ionic Group IIB organometallics (R2Cd and R2Zn; Volume 4, Chapter 1.2).
Journal of Organic Chemistry, Jul 1, 1979
Unnatural Cyclic Amino Acids was crystallized from n-hexane and then recrystallized from n-hexane... more Unnatural Cyclic Amino Acids was crystallized from n-hexane and then recrystallized from n-hexane-ethyl acetate to give the heptatriene 5 (50 mg, 50%); mp 166-167 "C. Concentration of the filtrate gave starting 7 (40 mg, 40%), mp 174-175 "C, from n-hexane. Both compounds gave satisfactory mixture melting points. X-Ray S t r u c t u r e of' Photoproduct B. Colorless crystals of tricyclophotoproduct 7 !were grown from a hexane solution. The crystal selected for structure analysis was a parallelepiped with approximate dimensions 0.30 X 0.23 X 0.23 mm and was mounted on a glass fiber with silicone adhesive. Precession photographs of this crystal led to a space group assignment of P2Jc with lattice constants of a = 1.4.813 (2) A, b = 10.717 (2) A, c = 16.827 (3) A, and p = 80.84 (21". The observed and calculated densities, assuming four molecules, of CS7Hm per unit cell volume, were 1.18 Data were collected on a Picker FACS 1 diffractometer by using the 0-28 scan technique with Zr-filtered Mo K a radiation and a takeoff angle of ,-2.5". Each of the 3774 independent data (28 5 45.77") was scanned 1.2" in 20 plus an allowance for spectral dispersion at a rate of l"/min, and backgrounds were of 20-s duration. Three standards inserted after every 100 reflections remained statistically constant. The data were reduced to a set of IF,l's by application of Lorentz and polarization corrections (L p). Standard deviations were calculated according to g/mL. OF = [(C' + k2B)/41F,1z(Lp)z]1/2 where C and B are the counts of scan and backgrounds, respectively, and k is the riitio of scan to background counting time. Some 2897 data with F, > 2aF were taken as observed and used in final stages of refinement. Normalized structure factor amplitudes [El's were calculated16 and the largest 400 were used in the reiterative application of the Sayre equati011.l~ Carbo11 atomic positions found from an E map1* were used in full-matrix isotropic refinement19,z@ followed by-(16) Program FAME by €1. Dewar and A. Stone was used. (17) Program REL by R. E. Long was used. (18) Program FORDAP by A. Zalkin was used.
Journal of the American Chemical Society, Jun 1, 1978
BENTHAM SCIENCE PUBLISHERS eBooks, Mar 26, 2012
Active efflux is a widespread mechanism for bacterial resistance to antibiotics, which contribute... more Active efflux is a widespread mechanism for bacterial resistance to antibiotics, which contributes to poor intrinsic susceptibility, cross-resistance to structurally diverse classes of drugs, or selection of other mechanisms of resistance. Thus, inhibition of efflux pumps appears to be (i) a promising strategy for restoring the activity of existing antibiotics, and (ii) a useful method to detect the presence of efflux determinants in clinical isolates. Structurally dissimilar classes of inhibitors have been patented in the last decade, some are analogs of antibiotic substrates [tetracyclines, quinolones or aminoglycosides] and others, new chemical entities [including substituted indoles, ureas, aromatic amides, piperidinecarboxylic acids, alkylamino-or alkoxyquinolines, peptidomimetics, and pyridopyrimidines]. Their spectrum of activity, in terms of antibiotics and bacteria, differ significantly. Narrow spectrum inhibitors are of prime interest as diagnostic tools, while broad spectrum inhibitors are expected for adjuvant therapies. Apart from (i) a peptidomimetic inhibitor of Mex pumps in Pseudomonas aeruginosa (MC-04,124), for which efficacy was evaluated in animal models, and (ii) a piperidinecarboxylic acid inhibitor of fluoroquinolone efflux in Gram-positive (VX-710), which was safely administered to humans, most of these products have only demonstrated their activity in vitro, so further investigations are needed to evaluate their clinical potential.
Journal of Medicinal Chemistry, Jul 1, 1991
Tazobactam (3, Cl&,,N40,S) is an effective inhibitor of bacterial 6-lactamases. It crystallizes w... more Tazobactam (3, Cl&,,N40,S) is an effective inhibitor of bacterial 6-lactamases. It crystallizes with unit cell dimensions a = 10.230 (2) A, b = 14.396 (2) A, and c = 17.291 (2) 8, in space group P2,2121. Compared to the related inhibitor sulbactam (2), which lacks the triazole ring, crystalline tazobactam exhibits very similar P-lactam geometry and the same S(1) envelope conformation of the thiazolidine ring. However, in both independent molecules of 3 a triazole ring nitrogen atom accepts an intermolecular hydrogen bond; similar interaction by this moiety of 3 with a hydrogen-bond donor on the enzyme, which is impossible for 2, could account for its enhanced inhibitory power. Semiempirical molecular orbital calculations show pronounced negative potential there. Molecular mechanics supports the hypothesis that the carboxyl group can rotate freely and the triazole ring can "flip".
Medicinal Research Reviews, Nov 1, 1999
Two discovery approaches directed to addressing the problem of increasing bacterial resistance ar... more Two discovery approaches directed to addressing the problem of increasing bacterial resistance are described. The first is a program to build activity against methicillin-resistant Staphylococcus aureus (MRSA) into the cephalosporin class of antibacterials, by enhancing affinity for PBP2a, the penicillin-binding protein responsible for this resistance. Through stepwise improvement in potency, human serum binding, solubility, and betalactamase stability, a stable of new compounds with excellent potential as anti-MRSA agents was realized. From this set was chosen MC-02, 479 (RWJ-54428), which is now undergoing extensive preclinical evaluation. The second approach explores the uridyl peptide family of antibiotics, inhibitors of bacterial translocase (mraY), whose members include the pacidamycins, mureidomycins, and napsamycins. Access to a diverse set of analogs by total synthesis was catalyzed by the discovery that hydrogenation of the 4'-exoenamidofuranosyl moiety causes no loss in biological activity. Indepth exploration of SAR required (1) establishment of the absolute stereochemistry of the central diaminobutyric acid (DABA) moiety and (2) determination of the stereochemistry of the 4'-substituent on the deoxyfuranose unit. The former was accomplished by comparison of DABA derived from degradation of a natural product pacidamycin with a sample synthesized from L-threonine. The biological activity of one member of a synthesized library of possible stereoisomers of the natural product established the absolute stereochemistry of the remaining centers. A variety of analogs of the natural product were prepared utilizing the synthetic methods developed, and their biological activities provide important insights into the specificity and spectrum of the antibiotic class.
ChemInform, Jul 14, 2010
ABSTRACT
Expert Opinion on Therapeutic Patents, Aug 1, 1995
The patent status of tetracycline research for the period of 1991 to 1995 is presented. Topics co... more The patent status of tetracycline research for the period of 1991 to 1995 is presented. Topics covered include new tetracyclines with intrinsic antibacterial activity against tetracycline-resistant bacteria or which potentiate the activity of the older tetracyclines, new natural products, new chemical methods, and non-infectious disease uses for tetracyclines.