Inhibitors of c-Kit kinase have shown clinical relevance in various myeloid disorders, including ... more Inhibitors of c-Kit kinase have shown clinical relevance in various myeloid disorders, including acute myeloid leukemia (AML). Research in our lab has been oriented towards structure-based drug design of c-Kit inhibitors based on the available crystal structure. We describe the design, synthesis, and preliminary results from the in-vitro testing of several c-Kit kinase inhibitors in both enzymatic and cell-based assays. The design resulted from in-silico screening of several targeted libraries via docking to the crystal structure of c-Kit, followed by aggressive post-filtering by several criteria to significantly bias synthesis efforts towards candidate compounds with best chance for success. This led to 128 structures built from 8 common structural cores, from which 2 cores were initially selected based on the synthetic feasibility. Five compounds were initially synthesized, and were immediately followed by 60 compounds with variations to probe local structure-activity relationships. The initial set of compounds, designated APCKxxx, was tested in a c-Kit kinase assay; two compounds were found to have an IC50 in the high nM to low uM range. These compounds have been tested in a MTT-based assay using OCIM2 and OCI/AML3 cell lines. In the c-Kit expressing OCI/AML3 cell line, all five compounds possessed an EC50 < 500 nM and two had and EC50 ~100 nM. Our most recent results show that these compounds also show efficacy in some imatinib-resistant cell lines. We will discuss these results and our strategies for the second generation of compounds that are optimized for better…
A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished in... more A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished involving intramolecular cyclisation of methyl 3-methyl-3-p-tolyl-6-bromohexanoate and in situ methylation of the resulting cyclopentanecarboxylate as the key reaction. A total synthesis of (±)-α-cuparenone has been achieved using α, α-dimethylation of methyl 3-methyl-3-p-tolyl-6,6ethylenedioxyhexanoate as a key step.
PDF file - 124 KB, Synthesis of Cromolyn Analogs:Lead compound C5OH synthesis is presented in mat... more PDF file - 124 KB, Synthesis of Cromolyn Analogs:Lead compound C5OH synthesis is presented in material and method sections. Other analogs synthesis procedure is provided as supplementary material.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
], Mohammed Namavari should have been listed as a co-author of the article. His colleagues regret... more ], Mohammed Namavari should have been listed as a co-author of the article. His colleagues regret the error.
], Mohammed Namavari should have been listed as a co-author of the article. His colleagues regret... more ], Mohammed Namavari should have been listed as a co-author of the article. His colleagues regret the error.
Start ing fro m 6-isopropyl-7-meth oxy-l-tetralo ne 2, a new sy nthesis of (±)-pi si feric ac id ... more Start ing fro m 6-isopropyl-7-meth oxy-l-tetralo ne 2, a new sy nthesis of (±)-pi si feric ac id 1 has bee n ac hi eved. The sali en t features of the present sy nth esis are (i) fac il e conversion of 2 into th e cis-fused oc tahydro phenanthreno ne 5, (ii) e ffi c ient transfo rm ati o n of 5 into the tri ester 7, and (iii) co nversio n o f 7 into 1 involving Dieckmann cycli sation as a key reac ti o n.
Jak kinases are non-receptor protein tyrosine kinases that play a pivotal role in cytokine/growth... more Jak kinases are non-receptor protein tyrosine kinases that play a pivotal role in cytokine/growth factor signaling through phosphorylation of specific proteins such as the Stat molecules. Activated Stats translocate to the nucleus where they mediate transcription of several target genes involved in cell cycle progression and survival (Bcl-xL, cyclin D1, c-myc, survivin. Many tumors have highly activated Stats that are associated with aberrant Jak2 regulation and recent studies have shown that activating mutations in Jak2 (V617F) play a key role in many myeloproliferative disorders such as polycythemia vera and essential thrombocythemia. Jak inhibitors may be useful in treating many diseases with aberrant Jak2/Stat signaling. The most commonly used inhibitor of Jak2 is the tyrphostin AG490, which inhibits Stat3 activation by preventing its tyrosine phosphorylation. However AG490 has limited in vivo efficacy and must be administered at high concentrations (>50 μM) for anti-tumor ef...
A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished in... more A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished involving intramolecular cyclisation of methyl 3-methyl-3-p-tolyl-6-bromohexanoate and in situ methylation of the resulting cyclopentanecarboxylate as the key reaction. A total synthesis of (±)-α-cuparenone has been achieved using α, α-dimethylation of methyl 3-methyl-3-p-tolyl-6,6ethylenedioxyhexanoate as a key step.
Inhibitors that inactivate specific tyrosine kinases have proven to be a very effective form of t... more Inhibitors that inactivate specific tyrosine kinases have proven to be a very effective form of therapy of many leukemias and hematopoetic disorders. Most inhibitors function by competing for the ATP-binding pocket or by preventing association with protein substrates. However, clinical and molecular studies have shown that small changes in the structure of the target kinase (point mutations, post-translational modification) affect inhibitor binding affinities, resulting in resistance to this class of inhibitor. Therefore, development of agents that reduce the activity of leukemogenic kinases through alternate mechanisms are of great interest. We previously described a novel class of compounds, termed degrasyns, which reduced BCR-ABL (and Jak2) kinase activity through a unique mechanism. Degrasyn treatment of CML or BaF3 cells expressing wild-type or mutant (T315I) BCR-ABL resulted in a reduction of cytoplasmic BCR-ABL protein levels and loss of downstream signaling without a direct ...
1045 Poster Board I-67 Kit is a type III receptor protein tyrosine kinase and membrane receptor f... more 1045 Poster Board I-67 Kit is a type III receptor protein tyrosine kinase and membrane receptor for stem cell factor (SCF). Tight regulation of the activity of kit is a crucial component of normal hematopoiesis. Mutations of the KIT gene have been identified in blasts of patients with AML predominantly those with core-binding factor leukemias. As the presence of mutations of KIT has been associated with higher likelihood of relapse and shorter survival, targeting Kit may be of therapeutic benefit. Therapeutic activity may extend to cases with Kit overexpression. We have recently described the activity of APcK110, a novel inhibitor of Kit, in vitro where we have shown potent proapoptotic and antiproliferative effects in AML cell lines and primary AML samples irrespective of mutation status but with measurable expression of Kit (Faderl S et al. Cancer Res 2009; 69: 3910-3917). Here we extend our investigations to the activity of APcK110 in vivo in a xenograft mouse model. After exposu...
Pro drugs are derivatives of drug substance which gives parent drug or release drug when it break... more Pro drugs are derivatives of drug substance which gives parent drug or release drug when it breaks inside the body by the presence of suitable enzyme,and then exert desired pharmacological effect. For many years, prodrug strategy has been developed enormously to solve many unwanted drug properties. In drug discovery and development, prodrugsare well-known pharmacokinetic effects of pharmacologically nimbleproducts. Almost10% of drugs permitted whole worldare classified as prodrugs, where the application of a prodrug method duringinitial stages of drug development is an emergent fashion. Phosphorodiamidates prodrugs are well known anticancer agents particularly against leucomia. To improve the selectivity of the chemotherapeutic agents and reduce systemic toxicity, I herein report different types of salicylate and salicylamide alcohols for the preparation of phosphorodiamidates and ifosfamide prodrugs.
The present review collects an update of the reactions in the area of medicinal chemistry using m... more The present review collects an update of the reactions in the area of medicinal chemistry using microwave irradiation. This review come up with an overview of most salient reactions performed under microwave irradiation in the field of drug discovery. Moreover, chemists are preferring to use this reaction rapidly in the academic as well as pharmaceutical laboratory during their drug discovery and making library of compounds. This reaction is much greener using less amount and readily recyclable solvents or sometimes reaction process without solvents and product become much cleaner, often yields are better than the conventional heating. Microwave irradiation is now very robust instrument used in company in the field of drug discovery, due to reduce the reaction time from hour to minute or even second and efficiently creation of compound libraries through combinatorial methodology associated with drug discovery so that new therapeutic agents bring to the market quicker. Hopefully, we ...
Prodrug is a very powerful way for the improvement of biopharmaceutical, physicochemical, or phar... more Prodrug is a very powerful way for the improvement of biopharmaceutical, physicochemical, or pharmacokinetic possessions of pharmacologically dynamic mediators. Prodrug is a pharmacologically not an active compound, which can be converted into an active drug by biotransformation which is metabolic and such process the efficiency of drugs gets improved with specific target delivery. The conversion of a prodrug to drug may happen before concentration, after concentration, or at a precise part of the physique. This approach has many advantages over drug administration which is in our convention. In this review, different types of carriers, which can be used for prodrug synthesis are summarized. Examples of both marketed and investigational prodrugs from several promoieties are discussed not only for their advantages and uses but also their prospects. The purpose of this review is to introduce in detail the foundation behind the use of the prodrug methodology from past to present, and a...
L'invention concerne des composes d'imagerie diagnostique in vivo de proliferation cellul... more L'invention concerne des composes d'imagerie diagnostique in vivo de proliferation cellulaire. Ces composes contiennent des L-nucleosides, tels qu'un analogue de nucleoside 2'-desoxy-2'-fluoro-L-arabinofuranosyl pyrimidine. Ces nucleosides sont marques au moyen d'un radio-isotope emettant des positrons. L'invention concerne egalement une methode d'imagerie diagnostique in vivo de proliferation cellulaire.
Inhibitors of c-Kit kinase have shown clinical relevance in various myeloid disorders, including ... more Inhibitors of c-Kit kinase have shown clinical relevance in various myeloid disorders, including acute myeloid leukemia (AML). Research in our lab has been oriented towards structure-based drug design of c-Kit inhibitors based on the available crystal structure. We describe the design, synthesis, and preliminary results from the in-vitro testing of several c-Kit kinase inhibitors in both enzymatic and cell-based assays. The design resulted from in-silico screening of several targeted libraries via docking to the crystal structure of c-Kit, followed by aggressive post-filtering by several criteria to significantly bias synthesis efforts towards candidate compounds with best chance for success. This led to 128 structures built from 8 common structural cores, from which 2 cores were initially selected based on the synthetic feasibility. Five compounds were initially synthesized, and were immediately followed by 60 compounds with variations to probe local structure-activity relationships. The initial set of compounds, designated APCKxxx, was tested in a c-Kit kinase assay; two compounds were found to have an IC50 in the high nM to low uM range. These compounds have been tested in a MTT-based assay using OCIM2 and OCI/AML3 cell lines. In the c-Kit expressing OCI/AML3 cell line, all five compounds possessed an EC50 < 500 nM and two had and EC50 ~100 nM. Our most recent results show that these compounds also show efficacy in some imatinib-resistant cell lines. We will discuss these results and our strategies for the second generation of compounds that are optimized for better…
A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished in... more A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished involving intramolecular cyclisation of methyl 3-methyl-3-p-tolyl-6-bromohexanoate and in situ methylation of the resulting cyclopentanecarboxylate as the key reaction. A total synthesis of (±)-α-cuparenone has been achieved using α, α-dimethylation of methyl 3-methyl-3-p-tolyl-6,6ethylenedioxyhexanoate as a key step.
PDF file - 124 KB, Synthesis of Cromolyn Analogs:Lead compound C5OH synthesis is presented in mat... more PDF file - 124 KB, Synthesis of Cromolyn Analogs:Lead compound C5OH synthesis is presented in material and method sections. Other analogs synthesis procedure is provided as supplementary material.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
], Mohammed Namavari should have been listed as a co-author of the article. His colleagues regret... more ], Mohammed Namavari should have been listed as a co-author of the article. His colleagues regret the error.
], Mohammed Namavari should have been listed as a co-author of the article. His colleagues regret... more ], Mohammed Namavari should have been listed as a co-author of the article. His colleagues regret the error.
Start ing fro m 6-isopropyl-7-meth oxy-l-tetralo ne 2, a new sy nthesis of (±)-pi si feric ac id ... more Start ing fro m 6-isopropyl-7-meth oxy-l-tetralo ne 2, a new sy nthesis of (±)-pi si feric ac id 1 has bee n ac hi eved. The sali en t features of the present sy nth esis are (i) fac il e conversion of 2 into th e cis-fused oc tahydro phenanthreno ne 5, (ii) e ffi c ient transfo rm ati o n of 5 into the tri ester 7, and (iii) co nversio n o f 7 into 1 involving Dieckmann cycli sation as a key reac ti o n.
Jak kinases are non-receptor protein tyrosine kinases that play a pivotal role in cytokine/growth... more Jak kinases are non-receptor protein tyrosine kinases that play a pivotal role in cytokine/growth factor signaling through phosphorylation of specific proteins such as the Stat molecules. Activated Stats translocate to the nucleus where they mediate transcription of several target genes involved in cell cycle progression and survival (Bcl-xL, cyclin D1, c-myc, survivin. Many tumors have highly activated Stats that are associated with aberrant Jak2 regulation and recent studies have shown that activating mutations in Jak2 (V617F) play a key role in many myeloproliferative disorders such as polycythemia vera and essential thrombocythemia. Jak inhibitors may be useful in treating many diseases with aberrant Jak2/Stat signaling. The most commonly used inhibitor of Jak2 is the tyrphostin AG490, which inhibits Stat3 activation by preventing its tyrosine phosphorylation. However AG490 has limited in vivo efficacy and must be administered at high concentrations (>50 μM) for anti-tumor ef...
A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished in... more A stereocontrolled total synthesis of (±)-tochuinyl acetate has been successfully accomplished involving intramolecular cyclisation of methyl 3-methyl-3-p-tolyl-6-bromohexanoate and in situ methylation of the resulting cyclopentanecarboxylate as the key reaction. A total synthesis of (±)-α-cuparenone has been achieved using α, α-dimethylation of methyl 3-methyl-3-p-tolyl-6,6ethylenedioxyhexanoate as a key step.
Inhibitors that inactivate specific tyrosine kinases have proven to be a very effective form of t... more Inhibitors that inactivate specific tyrosine kinases have proven to be a very effective form of therapy of many leukemias and hematopoetic disorders. Most inhibitors function by competing for the ATP-binding pocket or by preventing association with protein substrates. However, clinical and molecular studies have shown that small changes in the structure of the target kinase (point mutations, post-translational modification) affect inhibitor binding affinities, resulting in resistance to this class of inhibitor. Therefore, development of agents that reduce the activity of leukemogenic kinases through alternate mechanisms are of great interest. We previously described a novel class of compounds, termed degrasyns, which reduced BCR-ABL (and Jak2) kinase activity through a unique mechanism. Degrasyn treatment of CML or BaF3 cells expressing wild-type or mutant (T315I) BCR-ABL resulted in a reduction of cytoplasmic BCR-ABL protein levels and loss of downstream signaling without a direct ...
1045 Poster Board I-67 Kit is a type III receptor protein tyrosine kinase and membrane receptor f... more 1045 Poster Board I-67 Kit is a type III receptor protein tyrosine kinase and membrane receptor for stem cell factor (SCF). Tight regulation of the activity of kit is a crucial component of normal hematopoiesis. Mutations of the KIT gene have been identified in blasts of patients with AML predominantly those with core-binding factor leukemias. As the presence of mutations of KIT has been associated with higher likelihood of relapse and shorter survival, targeting Kit may be of therapeutic benefit. Therapeutic activity may extend to cases with Kit overexpression. We have recently described the activity of APcK110, a novel inhibitor of Kit, in vitro where we have shown potent proapoptotic and antiproliferative effects in AML cell lines and primary AML samples irrespective of mutation status but with measurable expression of Kit (Faderl S et al. Cancer Res 2009; 69: 3910-3917). Here we extend our investigations to the activity of APcK110 in vivo in a xenograft mouse model. After exposu...
Pro drugs are derivatives of drug substance which gives parent drug or release drug when it break... more Pro drugs are derivatives of drug substance which gives parent drug or release drug when it breaks inside the body by the presence of suitable enzyme,and then exert desired pharmacological effect. For many years, prodrug strategy has been developed enormously to solve many unwanted drug properties. In drug discovery and development, prodrugsare well-known pharmacokinetic effects of pharmacologically nimbleproducts. Almost10% of drugs permitted whole worldare classified as prodrugs, where the application of a prodrug method duringinitial stages of drug development is an emergent fashion. Phosphorodiamidates prodrugs are well known anticancer agents particularly against leucomia. To improve the selectivity of the chemotherapeutic agents and reduce systemic toxicity, I herein report different types of salicylate and salicylamide alcohols for the preparation of phosphorodiamidates and ifosfamide prodrugs.
The present review collects an update of the reactions in the area of medicinal chemistry using m... more The present review collects an update of the reactions in the area of medicinal chemistry using microwave irradiation. This review come up with an overview of most salient reactions performed under microwave irradiation in the field of drug discovery. Moreover, chemists are preferring to use this reaction rapidly in the academic as well as pharmaceutical laboratory during their drug discovery and making library of compounds. This reaction is much greener using less amount and readily recyclable solvents or sometimes reaction process without solvents and product become much cleaner, often yields are better than the conventional heating. Microwave irradiation is now very robust instrument used in company in the field of drug discovery, due to reduce the reaction time from hour to minute or even second and efficiently creation of compound libraries through combinatorial methodology associated with drug discovery so that new therapeutic agents bring to the market quicker. Hopefully, we ...
Prodrug is a very powerful way for the improvement of biopharmaceutical, physicochemical, or phar... more Prodrug is a very powerful way for the improvement of biopharmaceutical, physicochemical, or pharmacokinetic possessions of pharmacologically dynamic mediators. Prodrug is a pharmacologically not an active compound, which can be converted into an active drug by biotransformation which is metabolic and such process the efficiency of drugs gets improved with specific target delivery. The conversion of a prodrug to drug may happen before concentration, after concentration, or at a precise part of the physique. This approach has many advantages over drug administration which is in our convention. In this review, different types of carriers, which can be used for prodrug synthesis are summarized. Examples of both marketed and investigational prodrugs from several promoieties are discussed not only for their advantages and uses but also their prospects. The purpose of this review is to introduce in detail the foundation behind the use of the prodrug methodology from past to present, and a...
L'invention concerne des composes d'imagerie diagnostique in vivo de proliferation cellul... more L'invention concerne des composes d'imagerie diagnostique in vivo de proliferation cellulaire. Ces composes contiennent des L-nucleosides, tels qu'un analogue de nucleoside 2'-desoxy-2'-fluoro-L-arabinofuranosyl pyrimidine. Ces nucleosides sont marques au moyen d'un radio-isotope emettant des positrons. L'invention concerne egalement une methode d'imagerie diagnostique in vivo de proliferation cellulaire.
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