Kamil Paruch - Academia.edu (original) (raw)
Papers by Kamil Paruch
A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) i... more A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) inhibitors. From the invitro and cell-based analysis, the pyrazolo[1,5-a]pyrimidine core (represented by 9) emerged as the superior core for further elaboration in the identification of novel CDK2 inhibitors.
Tetrahedron Letters, 2014
Tetrahedron Letters, 2014
The Journal of Organic Chemistry, 2000
A procedure is described for synthesizing appreciable quantities of both the tetradodecyloxy[6]he... more A procedure is described for synthesizing appreciable quantities of both the tetradodecyloxy[6]helicenebisquinone 1 (R = dodecyl), which exhibits unique optical properties but previously was difficult to prepare, and a variety of analogues. The synthesis starts from disodium 4,5-dihydroxynaphthalene-2,7-disulfonate, the commercially available dye-intermediate known as chromotropic acid. It gives enantiopure 1, with R = (i-Pr)(3)Si, whose silyl groups can be replaced by dodecyl and hexanoyl groups. The same procedure applied to disodium 4-hydroxynaphthalene-2,7-disulfonate, also an inexpensive, commercially available chemical, works equally well to produce the corresponding molecules that have one fewer side chain. Key steps are the use of tosyl groups to protect phenols and of a method described seven years ago by Satoh, Itoh, Miura, and Nomura to transform the sulfonic acid functions to iodides. The structure of tetra-(1S)-camphanate 20, the ester of the reduction product of (-)-1 [R = (i-Pr)(3)Si], was analyzed by X-ray diffraction. It shows the absolute configurations and supports the presumed basis for the rule that the (1S)-camphanates of (P)-helicen-1-ols are more polar than their (M)-diastereomers.
The Journal of Organic Chemistry, 2000
ABSTRACT Alcohols containing HCl transform the hydroquinone reduction-products of helicenebisquin... more ABSTRACT Alcohols containing HCl transform the hydroquinone reduction-products of helicenebisquinones into p-alkoxyphenols that have the alkoxyls specifically on the peripheries of the helices. The reactions are quick, and the yields are high. Alkoxyls at the 6-position are replaced also, but only after 2 h at 60 °C, not after the 5 min at 25 °C sufficient to replace the peripheral hydroxyls of the hydroquinones. After the remaining inside hydroxyls of a dihydroxytetramethoxy[6]helicene prepared by this procedure have been converted into camphanates, one diastereomer crystallizes from solution, allowing an enantiomer resolution to be carried out on a large scale. By then simply reapplying the procedure with alcoholic acid, a variety of resolved dihydroxytetraalkoxy[6]helicenes can be prepared in excellent yields without resolution procedures having to be developed for each. Similar procedures are effective when applied to a [7]carbohelicene.
The Journal of …, 2003
Other polycyclic compounds Q 1150 Functionalizations of [6]-and [7]Helicenes at Their Most Steric... more Other polycyclic compounds Q 1150 Functionalizations of [6]-and [7]Helicenes at Their Most Sterically Hindered Positions. -(PARUCH, K.; VYKLICKY, L.; WANG, D. Z.; KATZ*, T. J.; INCARVITO, C.; ZAKHAROV, L.; RHEINGOLD, A. L.; J. Org. Chem. 68 (2003) 22, 8539-8544; Dep. Chem., Columbia Univ., New York, NY 10027, USA; Eng.) -Lindner 08-081
The Journal of …, 2000
Reported are the first examples of Friedel-Crafts reactions used to prepare 3,6-diacylphenanthren... more Reported are the first examples of Friedel-Crafts reactions used to prepare 3,6-diacylphenanthrenes. 9,10-Dimethoxyphenanthrene gives its 3,6-diacetyl derivative in good yield and in large amounts. The ketone's triisopropylsilyl enol ether when combined with 1, 4-benzoquinone forms a [7]helicenebisquinone. This bisquinone's reduction product, a bishydroquinone, when combined with methanolic HCl gives the [7]helicene whose peripheral side chains are all methoxyls but whose interior hydroxyls remain. The diastereomeric (1S)-(-)-camphanates can be separated by crystallization. Their structures, analyzed by X-ray diffraction, demonstrate that the camphanates' lactone functions point away from the ring system when the helicene has the (P) configuration and toward it when the helicene has the (M) configuration. This is because the camphanates' O=C-C-O dihedral angles are, as expected, close to 0 degrees in the former and close to 180 degrees in the latter. Other derivatives of 3,6-diacetylphenanthrene and of [7]helicenebisquinone are prepared, and the crystal structure of one of the latter is analyzed.
Current Computer Aided-Drug Design, 2013
A quantum mechanics (QM)-based scoring function has been applied to complexes of cyclin-dependent... more A quantum mechanics (QM)-based scoring function has been applied to complexes of cyclin-dependent kinase 2 (CDK2) and thirty-one pyrazolo[1,5-a]pyrimidine-based inhibitors and their bioisosteres. A hybrid three-layer QM/MM setup (DFT-D/PM6-D3H4X/AMBER in generalized Born solvent) was used here for the first time as an extension of our previous full QM and SQM/MM (SQM means semiempirical QM) approaches. Two approaches to obtain the structures of the CDK2/inhibitor complexes were examined: i) building the modifications from one X-ray structure available coupled with a conformational search and ii) docking the compounds into CDK2. The QM-based scoring entailed a QM/SQM/MM optimization followed by calculations of the binding scores which were subsequently correlated with the experimental binding free energies. The correlation for the building protocol was good (r(2) = 0.64, predictive index = 0.81), whereas the docking approach failed. A decomposition of the interaction energies to ligand fragments enabled us to rationalize the differences in the binding affinities. In conclusion, we have developed and refined a QM-based scoring protocol and successfully applied it to reproduce the binding affinities in congeneric series of CDK2 inhibitors and to rationalize their potency. We thus propose that such a tool can be used in computer-aided rational drug design.
Bioorganic & medicinal …, 2007
A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) i... more A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) inhibitors. From the in-vitro and cell-based analysis, the pyrazolo[1,5-a]pyrimidine core (represented by 9) emerged as the superior core for further elaboration in the ...
…, 2008
CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyraz... more CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding ...
Bioorganic & medicinal …, 2011
The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described l... more The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.
Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attracti... more Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent.
ACS Medicinal Chemistry Letters, 2010
Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the devel... more Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.
Bioorganic & Medicinal Chemistry Letters, 2007
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compoun... more Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.
A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) i... more A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) inhibitors. From the invitro and cell-based analysis, the pyrazolo[1,5-a]pyrimidine core (represented by 9) emerged as the superior core for further elaboration in the identification of novel CDK2 inhibitors.
Tetrahedron Letters, 2014
Tetrahedron Letters, 2014
The Journal of Organic Chemistry, 2000
A procedure is described for synthesizing appreciable quantities of both the tetradodecyloxy[6]he... more A procedure is described for synthesizing appreciable quantities of both the tetradodecyloxy[6]helicenebisquinone 1 (R = dodecyl), which exhibits unique optical properties but previously was difficult to prepare, and a variety of analogues. The synthesis starts from disodium 4,5-dihydroxynaphthalene-2,7-disulfonate, the commercially available dye-intermediate known as chromotropic acid. It gives enantiopure 1, with R = (i-Pr)(3)Si, whose silyl groups can be replaced by dodecyl and hexanoyl groups. The same procedure applied to disodium 4-hydroxynaphthalene-2,7-disulfonate, also an inexpensive, commercially available chemical, works equally well to produce the corresponding molecules that have one fewer side chain. Key steps are the use of tosyl groups to protect phenols and of a method described seven years ago by Satoh, Itoh, Miura, and Nomura to transform the sulfonic acid functions to iodides. The structure of tetra-(1S)-camphanate 20, the ester of the reduction product of (-)-1 [R = (i-Pr)(3)Si], was analyzed by X-ray diffraction. It shows the absolute configurations and supports the presumed basis for the rule that the (1S)-camphanates of (P)-helicen-1-ols are more polar than their (M)-diastereomers.
The Journal of Organic Chemistry, 2000
ABSTRACT Alcohols containing HCl transform the hydroquinone reduction-products of helicenebisquin... more ABSTRACT Alcohols containing HCl transform the hydroquinone reduction-products of helicenebisquinones into p-alkoxyphenols that have the alkoxyls specifically on the peripheries of the helices. The reactions are quick, and the yields are high. Alkoxyls at the 6-position are replaced also, but only after 2 h at 60 °C, not after the 5 min at 25 °C sufficient to replace the peripheral hydroxyls of the hydroquinones. After the remaining inside hydroxyls of a dihydroxytetramethoxy[6]helicene prepared by this procedure have been converted into camphanates, one diastereomer crystallizes from solution, allowing an enantiomer resolution to be carried out on a large scale. By then simply reapplying the procedure with alcoholic acid, a variety of resolved dihydroxytetraalkoxy[6]helicenes can be prepared in excellent yields without resolution procedures having to be developed for each. Similar procedures are effective when applied to a [7]carbohelicene.
The Journal of …, 2003
Other polycyclic compounds Q 1150 Functionalizations of [6]-and [7]Helicenes at Their Most Steric... more Other polycyclic compounds Q 1150 Functionalizations of [6]-and [7]Helicenes at Their Most Sterically Hindered Positions. -(PARUCH, K.; VYKLICKY, L.; WANG, D. Z.; KATZ*, T. J.; INCARVITO, C.; ZAKHAROV, L.; RHEINGOLD, A. L.; J. Org. Chem. 68 (2003) 22, 8539-8544; Dep. Chem., Columbia Univ., New York, NY 10027, USA; Eng.) -Lindner 08-081
The Journal of …, 2000
Reported are the first examples of Friedel-Crafts reactions used to prepare 3,6-diacylphenanthren... more Reported are the first examples of Friedel-Crafts reactions used to prepare 3,6-diacylphenanthrenes. 9,10-Dimethoxyphenanthrene gives its 3,6-diacetyl derivative in good yield and in large amounts. The ketone's triisopropylsilyl enol ether when combined with 1, 4-benzoquinone forms a [7]helicenebisquinone. This bisquinone's reduction product, a bishydroquinone, when combined with methanolic HCl gives the [7]helicene whose peripheral side chains are all methoxyls but whose interior hydroxyls remain. The diastereomeric (1S)-(-)-camphanates can be separated by crystallization. Their structures, analyzed by X-ray diffraction, demonstrate that the camphanates' lactone functions point away from the ring system when the helicene has the (P) configuration and toward it when the helicene has the (M) configuration. This is because the camphanates' O=C-C-O dihedral angles are, as expected, close to 0 degrees in the former and close to 180 degrees in the latter. Other derivatives of 3,6-diacetylphenanthrene and of [7]helicenebisquinone are prepared, and the crystal structure of one of the latter is analyzed.
Current Computer Aided-Drug Design, 2013
A quantum mechanics (QM)-based scoring function has been applied to complexes of cyclin-dependent... more A quantum mechanics (QM)-based scoring function has been applied to complexes of cyclin-dependent kinase 2 (CDK2) and thirty-one pyrazolo[1,5-a]pyrimidine-based inhibitors and their bioisosteres. A hybrid three-layer QM/MM setup (DFT-D/PM6-D3H4X/AMBER in generalized Born solvent) was used here for the first time as an extension of our previous full QM and SQM/MM (SQM means semiempirical QM) approaches. Two approaches to obtain the structures of the CDK2/inhibitor complexes were examined: i) building the modifications from one X-ray structure available coupled with a conformational search and ii) docking the compounds into CDK2. The QM-based scoring entailed a QM/SQM/MM optimization followed by calculations of the binding scores which were subsequently correlated with the experimental binding free energies. The correlation for the building protocol was good (r(2) = 0.64, predictive index = 0.81), whereas the docking approach failed. A decomposition of the interaction energies to ligand fragments enabled us to rationalize the differences in the binding affinities. In conclusion, we have developed and refined a QM-based scoring protocol and successfully applied it to reproduce the binding affinities in congeneric series of CDK2 inhibitors and to rationalize their potency. We thus propose that such a tool can be used in computer-aided rational drug design.
Bioorganic & medicinal …, 2007
A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) i... more A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) inhibitors. From the in-vitro and cell-based analysis, the pyrazolo[1,5-a]pyrimidine core (represented by 9) emerged as the superior core for further elaboration in the ...
…, 2008
CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyraz... more CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding ...
Bioorganic & medicinal …, 2011
The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described l... more The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.
Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attracti... more Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent.
ACS Medicinal Chemistry Letters, 2010
Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the devel... more Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.
Bioorganic & Medicinal Chemistry Letters, 2007
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compoun... more Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.