Iontcho Vlahov - Academia.edu (original) (raw)
Papers by Iontcho Vlahov
Chemical Communications, 2013
Bromination reactions have been made a lot more convenient since the invention of N-bromoamide re... more Bromination reactions have been made a lot more convenient since the invention of N-bromoamide reagents. These reagents are more easily handled when compared to molecular bromine. In comparison to other halogens, brominating reagents sit in between chlorine and iodine on the reactivity scale, giving them an advantage in some cases. Recently, several important advances in enantioselective bromofunctionalization of alkenes using such reagents have been reported. This article will highlight the challenges and methods to surmount these problems. In addition, this article will also show the use of N-bromoamide reagents in expanding the scope of diastereoselective bromofunctionalization of alkenes. Examples include bromine initiated cyclic ether cascades and novel multicomponent reactions (MCRs).
Journal of Carbohydrate Chemistry, 1997
ABSTRACT A highly regioselective conversion of sucrose into 6-O-acyl derivatives is reported. Fir... more ABSTRACT A highly regioselective conversion of sucrose into 6-O-acyl derivatives is reported. First sucrose was transformed into the dibutyltin acetal, thus enhancing the nucleophilicity at the C-6 oxygen and restricting the subsequent acylation reaction. The surface activity properties of the sucrose monoesters obtained were determined and compared with those of commercially available ionic and non-ionic surfactants.
ChemInform, Aug 4, 2010
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT 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.
Chemical Communications, 1998
By Giinther S n a t z k e [ * l Although chiroptical methods have been used in chemistry for some... more By Giinther S n a t z k e [ * l Although chiroptical methods have been used in chemistry for some 150 years, and the basic theory was developed by Rosenfeld 50 years ago, their success in determining absolute conformation rests mainly on empirical rules. Some of these can be proved theoretically ; however, in the case of more complex molecules this is not yet always possible. In what follows, an attempt is made to bridge the wide gap between theory and empiricism: "qualitative MO-theory", which has already been successfully used to explain reaction mechanisms, the shape of molecules, or photoelectron spectra, can also be applied to circular dichroism (CD). In general we shall have to be content with a reasonable interpretation of the experimentally determined sign correlation, but even this will be of great value since it can yield general relations between the geometry of molecules and the sign of CD. Such relations become particularly important when only a few examples of a given chromophore are known. If first and second sphere of a molecule are achiral then sector rules can be put forward, and in other cases helicity or chirality rules. 1. Chiroptical Phenomena Circular dichroism (CD) is nowadays the most frequently used chiroptical method [others involve e. g. measurement of optical rotation or optical rotatory dispersion, ellipticity, Raman-CID ("Raman Circular Intensity Differential"), CD p] Prof. Dr. G. Snatzke Lehrstuhl f i r Strukturchemie der Universitat Postfach 102148, D-4630 Bochum 1 (Germany)
Tetrahedron, Aug 1, 1998
Organocuprate, organozinc, organolithium, organotin and Grignard reagents have also been utilized... more Organocuprate, organozinc, organolithium, organotin and Grignard reagents have also been utilized for the C-glycosylation of sugar halides. I I Two examples,17 in Schemes 4 and 5, exemplify the methodology.
ChemInform, Aug 20, 2010
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.
Tetrahedron Letters, Nov 1, 1995
... We thank Dr. Toshihiko Toida for performing the NOE studies. 8382 REFERENCES AND NOTES: 1. He... more ... We thank Dr. Toshihiko Toida for performing the NOE studies. 8382 REFERENCES AND NOTES: 1. Heparin (Eds.: D. Lane, U. Lindahl), Edward Arnold, London, 1989; D. Grnitz, A. Yayon, J. Flanagan, C. Svahn, E. Levi, P. Leder, Mol. ... Tetrahedron Len. 21, 2135-2136 (1980). ...
Tetrahedron Letters, 1992
ABSTRACT
Tetrahedron Letters, Nov 1, 1991
ABSTRACT
Cancer Research, May 1, 2008
Cancer Research, 2006
568 The membrane-bound folate receptor (FR) is overexpressed on a wide range of primary and metas... more 568 The membrane-bound folate receptor (FR) is overexpressed on a wide range of primary and metastatic human cancers, such as those originating in ovary, lung, breast, endometrium, kidney and brain. Since folate-linked conjugates are known to be efficiently bound and internalized by FR-expressing cells, similar to the free vitamin, we have explored the possibility of using a single folate ligand to simultaneously target two small molecule chemotherapeutic drugs to the same FR. Herein we report the in vitro and in vivo evaluation of EC-0225, a novel folate conjugate of two drugs- one a potent microtubule inhibiting agent, and the second a DNA alkylating drug. When tested on cells in culture, EC-0225 was found to provide specific dose-dependent potency. Thus, EC-0225 inhibited the growth of FR-positive KB cells with an IC50 of ∼ 1 nM. The cytotoxic activity was greatly reduced in the presence of a large excess of folic acid. In addition, EC-0225 displayed no activity on FR-negative ce...
Cancer Research, 2008
2854 Cancer vaccine and immunotherapy rarely involve systemic administration of an immunogenic co... more 2854 Cancer vaccine and immunotherapy rarely involve systemic administration of an immunogenic compound in an actively immunized host. We have developed an active immunotherapy strategy that utilizes folic acid to deliver antigenic haptens (e.g. fluorescein, dinitrophenyl) to folate receptor-positive tumors in a host pre-vaccinated against the hapten. Such folate-targeted “haptenization” of tumor cell surfaces promotes their opsonization by endogenous anti-hapten antibodies, recruitment of immune effector cells, and subsequent removal of the tumor by the immune system. Although no allergic reactions to any folate-hapten conjugates had been observed in our preclinical studies, hapten-immunized mice were observed to produce a small amount of anti-hapten IgE antibody (an allergic Th2-type response); further, the systemic administration of folate-hapten formulations containing small amounts of multi-haptenated species was found to cause hypersensitivity responses in animal models of all...
Cell Reports Medicine, 2021
Summary Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled ... more Summary Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.
Scientific Reports, 2020
Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results... more Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patien...
Bioorganic & Medicinal Chemistry Letters, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Experimental and Molecular Therapeutics, 2019
Oncotarget, 2018
Purpose: The purpose was to determine the safety and antitumor activity of a folate-tubulysin con... more Purpose: The purpose was to determine the safety and antitumor activity of a folate-tubulysin conjugate (EC0531) in a relevant preclinical animal model, dogs with naturally-occurring invasive urothelial carcinoma (iUC). Canine iUC is an aggressive cancer with high folate receptor (FR) expression similar to that in certain forms of human cancer. Experimental Design: A 3+3 dose escalation study of EC0531 (starting dose 0.2 mg/kg given intravenously at two-week intervals) was performed in dogs with iUC expressing high levels of FRs (>50% positive tumor cells). Pharmacokinetic (PK) analysis was performed, and the maximum tolerated dose (MTD) was determined. The dose cohort at the MTD was expanded to determine antitumor activity. Results: The MTD of EC0531 was 0.26 mg/kg every two weeks, with grade 3-4 neutropenia and gastrointestinal toxicity observed at higher doses. Treatment at the MTD was well tolerated. Clinical benefit was found in 20 of 28 dogs (71%), including three dogs with partial remission and 17 dogs with stable disease. Plasma EC0531 concentrations in the dogs far exceeded those required to inhibit proliferation of FRexpressing cell in vitro. Unlike human neutrophils, canine neutrophils were found to express FRs, which contributes to the neutropenia at higher doses of EC0531 in dogs. Conclusion: EC0531 was well tolerated and had good antitumor activity in dogs with iUC. It is likely that humans will tolerate higher, potentially more effective doses of folate-tubulysin without myelotoxicity because of the absence of FRs on human neutrophils. The results clearly justify the evaluation of folate-tubulysin in human clinical trials.
Chemical Communications, 2013
Bromination reactions have been made a lot more convenient since the invention of N-bromoamide re... more Bromination reactions have been made a lot more convenient since the invention of N-bromoamide reagents. These reagents are more easily handled when compared to molecular bromine. In comparison to other halogens, brominating reagents sit in between chlorine and iodine on the reactivity scale, giving them an advantage in some cases. Recently, several important advances in enantioselective bromofunctionalization of alkenes using such reagents have been reported. This article will highlight the challenges and methods to surmount these problems. In addition, this article will also show the use of N-bromoamide reagents in expanding the scope of diastereoselective bromofunctionalization of alkenes. Examples include bromine initiated cyclic ether cascades and novel multicomponent reactions (MCRs).
Journal of Carbohydrate Chemistry, 1997
ABSTRACT A highly regioselective conversion of sucrose into 6-O-acyl derivatives is reported. Fir... more ABSTRACT A highly regioselective conversion of sucrose into 6-O-acyl derivatives is reported. First sucrose was transformed into the dibutyltin acetal, thus enhancing the nucleophilicity at the C-6 oxygen and restricting the subsequent acylation reaction. The surface activity properties of the sucrose monoesters obtained were determined and compared with those of commercially available ionic and non-ionic surfactants.
ChemInform, Aug 4, 2010
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT 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.
Chemical Communications, 1998
By Giinther S n a t z k e [ * l Although chiroptical methods have been used in chemistry for some... more By Giinther S n a t z k e [ * l Although chiroptical methods have been used in chemistry for some 150 years, and the basic theory was developed by Rosenfeld 50 years ago, their success in determining absolute conformation rests mainly on empirical rules. Some of these can be proved theoretically ; however, in the case of more complex molecules this is not yet always possible. In what follows, an attempt is made to bridge the wide gap between theory and empiricism: "qualitative MO-theory", which has already been successfully used to explain reaction mechanisms, the shape of molecules, or photoelectron spectra, can also be applied to circular dichroism (CD). In general we shall have to be content with a reasonable interpretation of the experimentally determined sign correlation, but even this will be of great value since it can yield general relations between the geometry of molecules and the sign of CD. Such relations become particularly important when only a few examples of a given chromophore are known. If first and second sphere of a molecule are achiral then sector rules can be put forward, and in other cases helicity or chirality rules. 1. Chiroptical Phenomena Circular dichroism (CD) is nowadays the most frequently used chiroptical method [others involve e. g. measurement of optical rotation or optical rotatory dispersion, ellipticity, Raman-CID ("Raman Circular Intensity Differential"), CD p] Prof. Dr. G. Snatzke Lehrstuhl f i r Strukturchemie der Universitat Postfach 102148, D-4630 Bochum 1 (Germany)
Tetrahedron, Aug 1, 1998
Organocuprate, organozinc, organolithium, organotin and Grignard reagents have also been utilized... more Organocuprate, organozinc, organolithium, organotin and Grignard reagents have also been utilized for the C-glycosylation of sugar halides. I I Two examples,17 in Schemes 4 and 5, exemplify the methodology.
ChemInform, Aug 20, 2010
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.
Tetrahedron Letters, Nov 1, 1995
... We thank Dr. Toshihiko Toida for performing the NOE studies. 8382 REFERENCES AND NOTES: 1. He... more ... We thank Dr. Toshihiko Toida for performing the NOE studies. 8382 REFERENCES AND NOTES: 1. Heparin (Eds.: D. Lane, U. Lindahl), Edward Arnold, London, 1989; D. Grnitz, A. Yayon, J. Flanagan, C. Svahn, E. Levi, P. Leder, Mol. ... Tetrahedron Len. 21, 2135-2136 (1980). ...
Tetrahedron Letters, 1992
ABSTRACT
Tetrahedron Letters, Nov 1, 1991
ABSTRACT
Cancer Research, May 1, 2008
Cancer Research, 2006
568 The membrane-bound folate receptor (FR) is overexpressed on a wide range of primary and metas... more 568 The membrane-bound folate receptor (FR) is overexpressed on a wide range of primary and metastatic human cancers, such as those originating in ovary, lung, breast, endometrium, kidney and brain. Since folate-linked conjugates are known to be efficiently bound and internalized by FR-expressing cells, similar to the free vitamin, we have explored the possibility of using a single folate ligand to simultaneously target two small molecule chemotherapeutic drugs to the same FR. Herein we report the in vitro and in vivo evaluation of EC-0225, a novel folate conjugate of two drugs- one a potent microtubule inhibiting agent, and the second a DNA alkylating drug. When tested on cells in culture, EC-0225 was found to provide specific dose-dependent potency. Thus, EC-0225 inhibited the growth of FR-positive KB cells with an IC50 of ∼ 1 nM. The cytotoxic activity was greatly reduced in the presence of a large excess of folic acid. In addition, EC-0225 displayed no activity on FR-negative ce...
Cancer Research, 2008
2854 Cancer vaccine and immunotherapy rarely involve systemic administration of an immunogenic co... more 2854 Cancer vaccine and immunotherapy rarely involve systemic administration of an immunogenic compound in an actively immunized host. We have developed an active immunotherapy strategy that utilizes folic acid to deliver antigenic haptens (e.g. fluorescein, dinitrophenyl) to folate receptor-positive tumors in a host pre-vaccinated against the hapten. Such folate-targeted “haptenization” of tumor cell surfaces promotes their opsonization by endogenous anti-hapten antibodies, recruitment of immune effector cells, and subsequent removal of the tumor by the immune system. Although no allergic reactions to any folate-hapten conjugates had been observed in our preclinical studies, hapten-immunized mice were observed to produce a small amount of anti-hapten IgE antibody (an allergic Th2-type response); further, the systemic administration of folate-hapten formulations containing small amounts of multi-haptenated species was found to cause hypersensitivity responses in animal models of all...
Cell Reports Medicine, 2021
Summary Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled ... more Summary Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.
Scientific Reports, 2020
Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results... more Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patien...
Bioorganic & Medicinal Chemistry Letters, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Experimental and Molecular Therapeutics, 2019
Oncotarget, 2018
Purpose: The purpose was to determine the safety and antitumor activity of a folate-tubulysin con... more Purpose: The purpose was to determine the safety and antitumor activity of a folate-tubulysin conjugate (EC0531) in a relevant preclinical animal model, dogs with naturally-occurring invasive urothelial carcinoma (iUC). Canine iUC is an aggressive cancer with high folate receptor (FR) expression similar to that in certain forms of human cancer. Experimental Design: A 3+3 dose escalation study of EC0531 (starting dose 0.2 mg/kg given intravenously at two-week intervals) was performed in dogs with iUC expressing high levels of FRs (>50% positive tumor cells). Pharmacokinetic (PK) analysis was performed, and the maximum tolerated dose (MTD) was determined. The dose cohort at the MTD was expanded to determine antitumor activity. Results: The MTD of EC0531 was 0.26 mg/kg every two weeks, with grade 3-4 neutropenia and gastrointestinal toxicity observed at higher doses. Treatment at the MTD was well tolerated. Clinical benefit was found in 20 of 28 dogs (71%), including three dogs with partial remission and 17 dogs with stable disease. Plasma EC0531 concentrations in the dogs far exceeded those required to inhibit proliferation of FRexpressing cell in vitro. Unlike human neutrophils, canine neutrophils were found to express FRs, which contributes to the neutropenia at higher doses of EC0531 in dogs. Conclusion: EC0531 was well tolerated and had good antitumor activity in dogs with iUC. It is likely that humans will tolerate higher, potentially more effective doses of folate-tubulysin without myelotoxicity because of the absence of FRs on human neutrophils. The results clearly justify the evaluation of folate-tubulysin in human clinical trials.