A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route s... more A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route starting from the known tricyclic diketones 2a-2d. Intermediary dibenzooxepin [4,5-d]imidazoles (3a, 3c) and dibenzothiepin [4,5-d]imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds 5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formylated at C(2) to afford 7a-7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric x-dimethylaminoalkyl derivatives 9a-9v. N-deprotection of 9i-9v led to the compounds 10a-10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be $11.5 and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their antiinflammatory activity.
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17b-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (B... more Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFb, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. In vitro BMP1-3 increased the expression of collagen type I and osteocalcin in MC3T3-E 1 osteoblast like cells, and enhanced the formation of mineralized bone nodules from bone marrow mesenchymal stem cells. We suggest that BMP1-3 is a novel systemic regulator of bone repair.
The compounds (VI) are tested in vitro for their anti-inflammatory activity through the inhibitio... more The compounds (VI) are tested in vitro for their anti-inflammatory activity through the inhibition of the necrosis factor alpha production (TNF-α) in lipopolysaccharide (LPS)-activated human peripheral blood monocular cells (hPBMC).
ii): (iii): POCl 3 /DMF X O Y H O N N X HN Y CHO Synthesis of a novel heterocyclic class of compo... more ii): (iii): POCl 3 /DMF X O Y H O N N X HN Y CHO Synthesis of a novel heterocyclic class of compounds, 1-aza-dibenzo[e,h]azulenes [1] (6a-c and 7a-c), derived from dibenzo[b,f]oxepin, its 8-chloro analogue and dibenzo[b,f]thiepin, respectively, is described.
Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1... more Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1 two novel classes of fused heterocyclic compounds, is described. Starting 11H-dibenzo[b,f]thiepin-10-one, 11H-dibenzo[b,f]oxepin-10-one and its 2-chloro derivative (1a-c) were oxidized to 1,2-diketones (2a-c)
Purpose. We have assessed the use of an ultrasonic nebulization system (UNS), composed of ultraso... more Purpose. We have assessed the use of an ultrasonic nebulization system (UNS), composed of ultrasonic nebulizer and diffusion dryer filled with charcoal, for the effective delivery of beclomethasone to the airways in a murine asthma model. Methods. Solution of beclomethasone in ethanol was aerosolized using an ultrasonic nebulizer. Passage of the aerosol through a drying column containing charcoal and deionizer produced dry beclomethasone particles. Particles were delivered to BALB/c mice placed in a whole-body exposition chamber 1 h before intranasal challenge with ovalbumine. Efficacy of beclomethasone delivery was evaluated by examining bronchoalveolar lavage fluid (BALF) cytology. Results. Effect of three UNS system parameters on aerosol particle size was investigated. The critical parameter affecting the size of dry particles was beclomethasone concentration in aerosolized solution and solution flow rate while power level of ultrasonic nebulizer generator had no effect. Administration of beclomethasone at calculated dose of 150 mg/kg to mice significantly decreased total cell number and relative eosinophil number in BALF.
ii): (iii): POCl 3 /DMF X O Y H O N N X HN Y CHO Synthesis of a novel heterocyclic class of compo... more ii): (iii): POCl 3 /DMF X O Y H O N N X HN Y CHO Synthesis of a novel heterocyclic class of compounds, 1-aza-dibenzo[e,h]azulenes [1] (6a-c and 7a-c), derived from dibenzo[b,f]oxepin, its 8-chloro analogue and dibenzo[b,f]thiepin, respectively, is described.
A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route s... more A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route starting from the known tricyclic diketones 2a-2d. Intermediary dibenzooxepin [4,5-d]imidazoles (3a, 3c) and dibenzothiepin [4,5-d]imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds 5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formylated at C(2) to afford 7a-7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric x-dimethylaminoalkyl derivatives 9a-9v. N-deprotection of 9i-9v led to the compounds 10a-10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be $11.5 and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their antiinflammatory activity.
Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1... more Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1 two novel classes of fused heterocyclic compounds, is described. Starting 11H-dibenzo[b,f]thiepin-10-one, 11H-dibenzo[b,f]oxepin-10-one and its 2-chloro derivative (1a-c) were oxidized to 1,2-diketones (2a-c)
Synthesis of four novel classes of structurally related fused hetero-pentacyclic compounds, napht... more Synthesis of four novel classes of structurally related fused hetero-pentacyclic compounds, naphtho[2,3-b]thieno[2,3-d][1]benzothiepins (Ia), naphtho[1,2-b]thieno[2,3-d][1]benzothiepins (IIa), naphtho[2,3-b]thieno-[2,3-d][1]benzoxepins (Ib,c) and naphtho[1,2-b]thieno[2,3-d][1]benzoxepins (IIb,c), is described. The key intermediates were the tetracyclic ketones,
Ribosome biogenesis has been associated with regulation of cell growth and cell division, but the... more Ribosome biogenesis has been associated with regulation of cell growth and cell division, but the molecular mechanisms that integrate the effect of ribosome biogenesis on these processes in mammalian cells remain unknown. To study the effect of impaired ribosome functions in vivo, we conditionally deleted one or two alleles of the 40S ribosomal protein S6 gene in T cells in the mouse. While complete deletion of S6 abrogated
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17b-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Biochemical and Biophysical Research Communications, 2011
Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (B... more Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFβ, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. In vitro BMP1-3 increased the expression of collagen type I
A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route s... more A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route starting from the known tricyclic diketones 2a-2d. Intermediary dibenzooxepin [4,5-d]imidazoles (3a, 3c) and dibenzothiepin [4,5-d]imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds 5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formylated at C(2) to afford 7a-7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric x-dimethylaminoalkyl derivatives 9a-9v. N-deprotection of 9i-9v led to the compounds 10a-10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be $11.5 and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their antiinflammatory activity.
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17b-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (B... more Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFb, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. In vitro BMP1-3 increased the expression of collagen type I and osteocalcin in MC3T3-E 1 osteoblast like cells, and enhanced the formation of mineralized bone nodules from bone marrow mesenchymal stem cells. We suggest that BMP1-3 is a novel systemic regulator of bone repair.
The compounds (VI) are tested in vitro for their anti-inflammatory activity through the inhibitio... more The compounds (VI) are tested in vitro for their anti-inflammatory activity through the inhibition of the necrosis factor alpha production (TNF-α) in lipopolysaccharide (LPS)-activated human peripheral blood monocular cells (hPBMC).
ii): (iii): POCl 3 /DMF X O Y H O N N X HN Y CHO Synthesis of a novel heterocyclic class of compo... more ii): (iii): POCl 3 /DMF X O Y H O N N X HN Y CHO Synthesis of a novel heterocyclic class of compounds, 1-aza-dibenzo[e,h]azulenes [1] (6a-c and 7a-c), derived from dibenzo[b,f]oxepin, its 8-chloro analogue and dibenzo[b,f]thiepin, respectively, is described.
Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1... more Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1 two novel classes of fused heterocyclic compounds, is described. Starting 11H-dibenzo[b,f]thiepin-10-one, 11H-dibenzo[b,f]oxepin-10-one and its 2-chloro derivative (1a-c) were oxidized to 1,2-diketones (2a-c)
Purpose. We have assessed the use of an ultrasonic nebulization system (UNS), composed of ultraso... more Purpose. We have assessed the use of an ultrasonic nebulization system (UNS), composed of ultrasonic nebulizer and diffusion dryer filled with charcoal, for the effective delivery of beclomethasone to the airways in a murine asthma model. Methods. Solution of beclomethasone in ethanol was aerosolized using an ultrasonic nebulizer. Passage of the aerosol through a drying column containing charcoal and deionizer produced dry beclomethasone particles. Particles were delivered to BALB/c mice placed in a whole-body exposition chamber 1 h before intranasal challenge with ovalbumine. Efficacy of beclomethasone delivery was evaluated by examining bronchoalveolar lavage fluid (BALF) cytology. Results. Effect of three UNS system parameters on aerosol particle size was investigated. The critical parameter affecting the size of dry particles was beclomethasone concentration in aerosolized solution and solution flow rate while power level of ultrasonic nebulizer generator had no effect. Administration of beclomethasone at calculated dose of 150 mg/kg to mice significantly decreased total cell number and relative eosinophil number in BALF.
ii): (iii): POCl 3 /DMF X O Y H O N N X HN Y CHO Synthesis of a novel heterocyclic class of compo... more ii): (iii): POCl 3 /DMF X O Y H O N N X HN Y CHO Synthesis of a novel heterocyclic class of compounds, 1-aza-dibenzo[e,h]azulenes [1] (6a-c and 7a-c), derived from dibenzo[b,f]oxepin, its 8-chloro analogue and dibenzo[b,f]thiepin, respectively, is described.
A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route s... more A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route starting from the known tricyclic diketones 2a-2d. Intermediary dibenzooxepin [4,5-d]imidazoles (3a, 3c) and dibenzothiepin [4,5-d]imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds 5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formylated at C(2) to afford 7a-7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric x-dimethylaminoalkyl derivatives 9a-9v. N-deprotection of 9i-9v led to the compounds 10a-10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be $11.5 and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their antiinflammatory activity.
Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1... more Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1 two novel classes of fused heterocyclic compounds, is described. Starting 11H-dibenzo[b,f]thiepin-10-one, 11H-dibenzo[b,f]oxepin-10-one and its 2-chloro derivative (1a-c) were oxidized to 1,2-diketones (2a-c)
Synthesis of four novel classes of structurally related fused hetero-pentacyclic compounds, napht... more Synthesis of four novel classes of structurally related fused hetero-pentacyclic compounds, naphtho[2,3-b]thieno[2,3-d][1]benzothiepins (Ia), naphtho[1,2-b]thieno[2,3-d][1]benzothiepins (IIa), naphtho[2,3-b]thieno-[2,3-d][1]benzoxepins (Ib,c) and naphtho[1,2-b]thieno[2,3-d][1]benzoxepins (IIb,c), is described. The key intermediates were the tetracyclic ketones,
Ribosome biogenesis has been associated with regulation of cell growth and cell division, but the... more Ribosome biogenesis has been associated with regulation of cell growth and cell division, but the molecular mechanisms that integrate the effect of ribosome biogenesis on these processes in mammalian cells remain unknown. To study the effect of impaired ribosome functions in vivo, we conditionally deleted one or two alleles of the 40S ribosomal protein S6 gene in T cells in the mouse. While complete deletion of S6 abrogated
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent gluco... more A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17b-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Biochemical and Biophysical Research Communications, 2011
Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (B... more Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFβ, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. In vitro BMP1-3 increased the expression of collagen type I
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