The Experts below are selected from a list of 1026 Experts worldwide ranked by ideXlab platform
Dale L. Boger - One of the best experts on this subject based on the ideXlab platform.
-
synthesis and evaluation of Duocarmycin sa analogs incorporating the methyl 1 2 8 8a tetrahydrocyclopropa c imidazolo 4 5 e indol 4 one 6 carboxylate cimi alkylation subunit
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Prem B Chanda, Kristopher E Boyle, Daniel M Brody, Vyom Shukla, Dale L. BogerAbstract:The design, synthesis, and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) derivatives are detailed representing analogs of Duocarmycin SA and yatakemycin containing an imidazole replacement for the fused pyrrole found in the DNA alkylation subunit.
-
Printed in Great Britain.
2015Co-Authors: Dale L. Boger, Duocarmydn C, Pyrindamycin A, D. L. BogerAbstract:Design, synthesis, and evaluation of DNA minor groove binding agents: the Duocarmycin
-
Synthesis and evaluation of a series of C5′-substituted Duocarmycin SA analogs
Bioorganic & medicinal chemistry letters, 2010Co-Authors: William M. Robertson, Inkyu Hwang, David B. Kastrinsky, Dale L. BogerAbstract:Abstract The synthesis and evaluation of a key series of analogs of Duocarmycin SA, bearing a single substituent at the C5′ position of the DNA binding subunit, are described.
-
synthesis and evaluation of Duocarmycin sa analogs incorporating the methyl 1 2 8 8a tetrahydrocyclopropa c oxazolo 2 3 e indol 4 one 6 carboxylate coi alkylation subunit
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Kristopher E Boyle, Karen S. Macmillan, William M. Robertson, James P. Lajiness, David Archer Ellis, Dale L. BogerAbstract:The design, synthesis and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) derivatives are detailed representing analogs of Duocarmycin SA containing an oxazole replacement for the fused pyrrole found in the alkylation subunit.
-
Synthesis and Evaluation of a Thio Analogue of Duocarmycin SA
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Karen S. Macmillan, Inkyu Hwang, William M. Robertson, Romeo Romagnoli, Pier Giovanni Baraldi, James P. Lajiness, Carlota Lopez Cara, Dale L. BogerAbstract:The design, synthesis, and preliminary evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one-6-carboxylate (CTI) derivatives are detailed representing a single atom change (N to S) embedded in the Duocarmycin SA alkylation subunit.
Mark Searcey - One of the best experts on this subject based on the ideXlab platform.
-
CHAPTER 9:Duocarmycins as Antibody–Drug Conjugate (ADC) Payloads
Cytotoxic Payloads for Antibody–Drug Conjugates, 2019Co-Authors: Andrew M. Beekman, Marco M. D. Cominetti, Mark SearceyAbstract:The Duocarmycins are a family of natural products first described in 1978 with the discovery of CC-1065. These DNA alkylating spirocyclopropyl-cyclohexadienones demonstrate ultrapotent cytotoxic activity, provided by the sequence-selective alkylation of the N3 of adenine. The medicinal chemistry community immediately saw great potential in the picomolar potency of the Duocarmycins in cell lines, but inherent toxicity in vivo has hindered their progression through to clinical use. Consequently, a variety of strategies have been developed to harness the power of the Duocarmycins and to begin to realise the potential of their highly interesting mode of action, the most exciting of which is the development of antibody–drug conjugates (ADCs). This chapter will present the most recent understanding of the mechanism of action of the Duocarmycins and the downstream effects of DNA alkylation. Innovative approaches to the synthesis of the Duocarmycins, including stereoselective synthesis and new approaches for solid-phase synthesis, are discussed. This chapter also highlights the approaches of medicinal chemists to harness the Duocarmycins for clinical use and an overview of prodrug strategies is presented, emphasising the most effective and creative methods to release the Duocarmycins at the desired site of action. Finally, the use of Duocarmycins as ADCs is reviewed, underlining the inventive chemical approaches to direct and deliver this ultrapotent payload.
-
Solid-phase synthesis of Duocarmycin analogues and the effect of C-terminal substitution on biological activity
The Journal of organic chemistry, 2015Co-Authors: Michael J. Stephenson, Lesley A. Howell, Maria A. O'connell, Keith R. Fox, Claire Adcock, Jenny Kingston, Helen M. Sheldrake, Klaus Pors, Stephen Paul Collingwood, Mark SearceyAbstract:The Duocarmycins are potent antitumor agents with potential for use in the development of antibody–drug conjugates (ADCs) as well as being clinical candidates in their own right. In this article, we describe the synthesis of a Duocarmycin monomer (DSA) that is suitably protected for utilization in solid-phase synthesis. The synthesis was performed on a large scale, and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers; its application to solid-phase synthesis methodology gave a series of monomeric and extended Duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to that in previous reports for both the monomeric and extended compounds. Substitution at the C-terminus of Duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure...
-
Abstract 4541: Tumor-selective bioactivation of Duocarmycin bioprecursors by cytochrome P450 enzymes provides an opportunity to treat drug-resistant breast cancer cells
Cancer Chemistry, 2015Co-Authors: Steven D. Shnyder, Helen M. Sheldrake, Mark Searcey, Paul M. Loadman, Mark Sutherland, Laurence H. Patterson, Klaus PorsAbstract:Background The cytochrome P450 (CYP) enzymes are responsible for the oxidation of a diverse range of xenobiotic and endogenous compounds. The high expression of CYP1A1, 1B1 and 2W1 in tumour tissue and surrounding stroma compared to nearby normal tissue provides an opportunity for development of selective cancer therapeutics. The ultrapotent Duocarmycins are ideal candidates for bioprecursor development and we have demonstrated that these can be re-engineered into derivatives selectively activated by CYP1A1, 1B1 (unpublished) and 2W1 in vitro and in vivo.1-3 Materials and methods Standard material and methods can be found in the references below. Briefly, these include synthetic chemistry necessary for synthesis of Duocarmycin bioprecursors, use of recombinant CYP bactosomes for metabolite identification using LC/MS and cell culture experiments using the MTT assay. Results In the present study, we have focussed on the potential of eradicating both sensitive and drug-resistant breast cancer cells (MCF-7, MDA-MB-468 and MDA-MB-231). We have evaluated a library of novel compounds in vitro and shown 3-modified CPI bioprecursors to be bioactivated to potent ( Conclusion Modifications to the structure of the seco-Duocarmycins influences the extent of their CYP-mediated activation and indicates their potential for breast cancer chemotherapy. [1] Sheldrake et al. Re-engineering of the Duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity. J Med Chem. 2013, 56, 6273-7. [2] Travica et al. Colon cancer-specific cytochrome P450 2W1 converts Duocarmycin analogues into potent tumor cytotoxins. Clin Cancer Res. 2013, 19, 2952-61. [3] Pors et al. Modification of the Duocarmycin pharmacophore enables CYP1A1 targeting for biological activity. Chem Commun. 2011, 47, 12062-4. Citation Format: Steven D. Shnyder, Paul M. Loadman, Mark Sutherland, Helen M. Sheldrake, Mark Searcey, Laurence H. Patterson, Klaus Pors. Tumor-selective bioactivation of Duocarmycin bioprecursors by cytochrome P450 enzymes provides an opportunity to treat drug-resistant breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4541. doi:10.1158/1538-7445.AM2015-4541
-
Solid-Phase Synthesis of Duocarmycin Analogues and the Effect of C‑Terminal Substitution on Biological Activity
2015Co-Authors: Michael J. Stephenson, Lesley A. Howell, Keith R. Fox, Claire Adcock, Jenny Kingston, Helen M. Sheldrake, Klaus Pors, Stephen Paul Collingwood, Maria A. O’connell, Mark SearceyAbstract:The Duocarmycins are potent antitumor agents with potential for use in the development of antibody–drug conjugates (ADCs) as well as being clinical candidates in their own right. In this article, we describe the synthesis of a Duocarmycin monomer (DSA) that is suitably protected for utilization in solid-phase synthesis. The synthesis was performed on a large scale, and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers; its application to solid-phase synthesis methodology gave a series of monomeric and extended Duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to that in previous reports for both the monomeric and extended compounds. Substitution at the C-terminus of Duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine, but this had no beneficial effects on biological activity
-
abstract 2224 re engineering of the Duocarmycin structural architecture enables tumour selective cyp2w1 mediated drug activation in human colon cancer xenografts
Cancer Research, 2013Co-Authors: Klaus Pors, Helen M. Sheldrake, Mark Searcey, Steven D. Shnyder, Paul M. Loadman, Mark Sutherland, Inger Johansson, Souren Mkrtchian, Sandra Travica, Magnus IngelmansundbergAbstract:There is now growing evidence that CYP1A1, 1B1, 2J2, 2S1 and 2W1 are over-expressed in many human tumour types. The ultrapotent Duocarmycins are ideal candidates for bioprecursor drug development and we have demonstrated that these can be re-engineered into derivatives selectively activated by CYP1A1 in vitro and in vivo. 1 , 2 In the present study, we have focussed on CYP2W1 as a potential therapeutic target. CYP2W1 is detected in 30% of colon cancers, while its protein expression in non-transformed adult tissues is absent or insignificant. 3 We have presented results indicating that the immunohistochemically assessed level of CYP2W1 enzyme could fulfil the criteria for being a prognostic biomarker for stages II and III colorectal cancer. 4 Here we present data on furanoindole-based Duocarmycins that have the potential to be used as a chemical probe (e.g. ICT2726) to show CYP2W1 functional activity. We also report on indoline-based analogues that elicit potent antiproliferative activity after CYP2W1-mediated activation in cancer cells. Specifically, we have transfected human HEK293, Colo320 and SW480 cells to express CYP2W1 and shown that these suffer rapid loss of viability following treatment with two halogenated Duocarmycin bioprecursor compounds (ICT2705 and ICT2706) while no activity in mock-transfected cells was seen. Significantly, ICT2706 was shown to totally prevent tumour growth when administered to SCID mice bearing SW480-2W1 xenografts (dosed daily with 100 mg/kg for 8 days) but not the mock-transfected variant. Subsequent to this treatment, the tumours were extracted for further analysis. Using H2A.X phosphorylation as a marker for DNA damage, our data revealed a time-dependent increase in expression supporting CYP2W1-mediated activation of ICT2706 in vivo. Our findings reveal the opportunities in targeting CYP2W1 as a novel therapeutic approach in colon cancer chemotherapy. Citation Format: Klaus Pors, Sandra Travica, Paul M. Loadman, Steven D. Shnyder, Mark Sutherland, Helen M. Sheldrake, Mark Searcey, Inger Johansson, Souren Mkrtchian, Magnus IngelmanSundberg, Laurence H. Patterson. Re-engineering of the Duocarmycin structural architecture enables tumour-selective CYP2W1-mediated drug activation in human colon cancer xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2224. doi:10.1158/1538-7445.AM2013-2224
Hiromitsu Saito - One of the best experts on this subject based on the ideXlab platform.
-
Synthesis and antitumor activity of Duocarmycin derivatives: modification at the C-7 position of segment-A of A-ring pyrrole compounds
Bioorganic & medicinal chemistry, 2000Co-Authors: Nobuyoshi Amishiro, Akihiko Okamoto, Masami Okabe, Hiromitsu SaitoAbstract:A series of the C7-substituted A-ring pyrrole derivatives of Duocarmycin were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. All of the C7-substituted A-ring pyrrole compounds decreased potency in vitro and in vivo. However, some showed strong antitumor activity with T/C values less than 0.3. Among them, the 7-formyl compound 5d Scheme 1. (a) NBS or NCS, CCl4, rt; (b) Ac2O, BF3·Et2O, rt; (c) Cl2CHOMe, TiCl4, CH2Cl2, rt; (d) MeOCH2COCl, AlCl3, CH2Cl2, rt; (e) NaNO2, AcOH, dioxane, −20 °C; (f) 1) NaH, 2) p-nitrophenyl 4-methoxycinnamate, DMF, −20 °C; (g) 1) HCl, 2) 4-methoxycinnamic acid, EDCI, rt; (h) DBU, CH3CN, rt. Figure options Download full-size image Download high-quality image (140 K) Download as PowerPoint slide showed remarkable potent in vivo antitumor activity and low peripheral blood toxicity, which were equal to 2c Figure 1. Structure of Duocarmycins and Duocarmycin derivatives. Figure options Download full-size image Download high-quality image (106 K) Download as PowerPoint slide .
-
Synthesis and antitumor activity of water-soluble Duocarmycin B1 prodrugs
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Akira Asai, Satoru Nagamura, Eiji Kobayashi, Katsushige Gomi, Hiromitsu SaitoAbstract:The water-soluble Duocarmycin B1 prodrugs such as glycoside 3, phosphate 4 and carbamate 5 were synthesized for improving biological and pharmaceutical profiles of Duocarmycin. Among these prodrugs, N-methylpiperazinylcarbamoyl derivative 5 exhibited potent antitumor activity against several human tumors in vivo.
-
Synthesis and antitumor activity of Duocarmycin derivatives: modification of segment-A of A-ring pyrrole compounds.
Journal of medicinal chemistry, 1999Co-Authors: Nobuyoshi Amishiro, Akihiko Okamoto, Masami Okabe, Chikara Murakata, Tatsuya Tamaoki, Hiromitsu SaitoAbstract:A series of 3-substituted A-ring pyrrole compounds of Duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S 3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among 3-substituted A-ring pyrrole compounds of Duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole Duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.
-
New Water-Soluble Duocarmycin Derivatives: Synthesis and Antitumor Activity of A-Ring Pyrrole Compounds Bearing β-Heteroarylacryloyl Groups
Journal of medicinal chemistry, 1999Co-Authors: Nobuyoshi Amishiro, Satoru Nagamura, Eiji Kobayashi, Katsushige Gomi, Hiromitsu SaitoAbstract:A series of A-ring pyrrole compounds of Duocarmycin bearing 4‘-methoxy-β-heteroarylacryloyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in viv...
-
Synthesis and Antitumor Activity of Duocarmycin Derivatives: A-Ring Pyrrole Compounds Bearing Cinnamoyl Groups
Journal of medicinal chemistry, 1997Co-Authors: Satoru Nagamura, Akira Asai, Nobuyoshi Amishiro, Eiji Kobayashi, Katsushige Gomi, Hiromitsu SaitoAbstract:A series of N-cinnamates of the A-ring pyrrole compound of Duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. The 4‘-methoxy- and 4‘-BocNH-cinnamates exhibited strong in vitro anticellular activity among the synthesized compounds. The ortho substitution of the 4‘-methoxycinnamate did not affect the anticellular activity and contributed to an enhancement of water solubility. Most of the 8-O-(N,N-dialkylcarbamoyl) derivatives of the 4‘-methoxycinnamates displayed remarkably superior in vivo antitumor activity to Duocarmycin A or B2. Moreover, it is noteworthy that these 8-O-(N,N-dialkylcarbamoyl) derivatives exhibited significant antitumor activity at wider range of doses as compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment B.
Inkyu Hwang - One of the best experts on this subject based on the ideXlab platform.
-
Synthesis and evaluation of a series of C5′-substituted Duocarmycin SA analogs
Bioorganic & medicinal chemistry letters, 2010Co-Authors: William M. Robertson, Inkyu Hwang, David B. Kastrinsky, Dale L. BogerAbstract:Abstract The synthesis and evaluation of a key series of analogs of Duocarmycin SA, bearing a single substituent at the C5′ position of the DNA binding subunit, are described.
-
Synthesis and Evaluation of a Thio Analogue of Duocarmycin SA
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Karen S. Macmillan, Inkyu Hwang, William M. Robertson, Romeo Romagnoli, Pier Giovanni Baraldi, James P. Lajiness, Carlota Lopez Cara, Dale L. BogerAbstract:The design, synthesis, and preliminary evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one-6-carboxylate (CTI) derivatives are detailed representing a single atom change (N to S) embedded in the Duocarmycin SA alkylation subunit.
-
Total synthesis and evaluation of iso-Duocarmycin SA and iso-yatakemycin.
Journal of the American Chemical Society, 2009Co-Authors: Karen S. Macmillan, Inkyu Hwang, Trihn Nguyen, Dale L. BogerAbstract:The total synthesis and evaluation of iso-Duocarmycin SA (5) and iso-yatakemycin (6), representing key analogues of the corresponding natural products incorporating an isomeric alkylation subunit, are detailed. This pyrrole isomer of the natural alkylation subunit displayed an enhanced reaction regioselectivity and a 2-fold diminished stability. Although still exceptionally potent, the iso-Duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3−5-fold reduction in cytotoxic activity [L1210 IC50 for (+)-iso-Duocarmycin SA = 50 pM and for (+)-iso-yatakemycin = 15 pM] consistent with their placement on a parabolic relationship correlating activity with reactivity. The DNA alkylation selectivity of the resulting key natural product analogues was unaltered by the structure modification in spite of the minor-groove presentation of a potential H-bond donor. Additionally, a unique ortho-spirocyclization with such derivatives was explored via the preparation, characterizati...
-
asymmetric total synthesis of and ent yatakemycin and Duocarmycin sa evaluation of yatakemycin key partial structures and its unnatural enantiomer
Journal of the American Chemical Society, 2006Co-Authors: Mark S Tichenor, David B. Kastrinsky, Inkyu Hwang, John David Trzupek, Futoshi Shiga, Dale L. BogerAbstract:Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of Duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-Duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five-base-pair AT sequence, e.g., 5‘-AAAAA), efficiency, relative rate, and reversibility of ent-(−)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nat...
-
Asymmetric Total Synthesis of (+)- and ent-(−)-Yatakemycin and Duocarmycin SA: Evaluation of Yatakemycin Key Partial Structures and Its Unnatural Enantiomer
Journal of the American Chemical Society, 2006Co-Authors: Mark S Tichenor, David B. Kastrinsky, Inkyu Hwang, John David Trzupek, Futoshi Shiga, Dale L. BogerAbstract:Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of Duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-Duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five-base-pair AT sequence, e.g., 5‘-AAAAA), efficiency, relative rate, and reversibility of ent-(−)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nat...
Klaus Pors - One of the best experts on this subject based on the ideXlab platform.
-
How can the potential of the Duocarmycins be unlocked for cancer therapy?
Drug discovery today, 2020Co-Authors: Zoë Jukes, Paul M. Loadman, Goreti Ribeiro Morais, Klaus PorsAbstract:The Duocarmycins belong to a class of agent that has fascinated scientists for over four decades. Their exquisite potency, unique mechanism of action, and efficacy in multidrug-resistant tumour models makes them attractive to medicinal chemists and drug hunters. However, despite great advances in fine-tuning biological activity through structure-activity relationship studies (SARS), no Duocarmycin-based therapeutic has reached clinical approval. In this review, we provide an overview of the most promising strategies currently used and include both tumour-targeted prodrug approaches and antibody-directed technologies.
-
Solid-phase synthesis of Duocarmycin analogues and the effect of C-terminal substitution on biological activity
The Journal of organic chemistry, 2015Co-Authors: Michael J. Stephenson, Lesley A. Howell, Maria A. O'connell, Keith R. Fox, Claire Adcock, Jenny Kingston, Helen M. Sheldrake, Klaus Pors, Stephen Paul Collingwood, Mark SearceyAbstract:The Duocarmycins are potent antitumor agents with potential for use in the development of antibody–drug conjugates (ADCs) as well as being clinical candidates in their own right. In this article, we describe the synthesis of a Duocarmycin monomer (DSA) that is suitably protected for utilization in solid-phase synthesis. The synthesis was performed on a large scale, and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers; its application to solid-phase synthesis methodology gave a series of monomeric and extended Duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to that in previous reports for both the monomeric and extended compounds. Substitution at the C-terminus of Duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure...
-
Abstract 4541: Tumor-selective bioactivation of Duocarmycin bioprecursors by cytochrome P450 enzymes provides an opportunity to treat drug-resistant breast cancer cells
Cancer Chemistry, 2015Co-Authors: Steven D. Shnyder, Helen M. Sheldrake, Mark Searcey, Paul M. Loadman, Mark Sutherland, Laurence H. Patterson, Klaus PorsAbstract:Background The cytochrome P450 (CYP) enzymes are responsible for the oxidation of a diverse range of xenobiotic and endogenous compounds. The high expression of CYP1A1, 1B1 and 2W1 in tumour tissue and surrounding stroma compared to nearby normal tissue provides an opportunity for development of selective cancer therapeutics. The ultrapotent Duocarmycins are ideal candidates for bioprecursor development and we have demonstrated that these can be re-engineered into derivatives selectively activated by CYP1A1, 1B1 (unpublished) and 2W1 in vitro and in vivo.1-3 Materials and methods Standard material and methods can be found in the references below. Briefly, these include synthetic chemistry necessary for synthesis of Duocarmycin bioprecursors, use of recombinant CYP bactosomes for metabolite identification using LC/MS and cell culture experiments using the MTT assay. Results In the present study, we have focussed on the potential of eradicating both sensitive and drug-resistant breast cancer cells (MCF-7, MDA-MB-468 and MDA-MB-231). We have evaluated a library of novel compounds in vitro and shown 3-modified CPI bioprecursors to be bioactivated to potent ( Conclusion Modifications to the structure of the seco-Duocarmycins influences the extent of their CYP-mediated activation and indicates their potential for breast cancer chemotherapy. [1] Sheldrake et al. Re-engineering of the Duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity. J Med Chem. 2013, 56, 6273-7. [2] Travica et al. Colon cancer-specific cytochrome P450 2W1 converts Duocarmycin analogues into potent tumor cytotoxins. Clin Cancer Res. 2013, 19, 2952-61. [3] Pors et al. Modification of the Duocarmycin pharmacophore enables CYP1A1 targeting for biological activity. Chem Commun. 2011, 47, 12062-4. Citation Format: Steven D. Shnyder, Paul M. Loadman, Mark Sutherland, Helen M. Sheldrake, Mark Searcey, Laurence H. Patterson, Klaus Pors. Tumor-selective bioactivation of Duocarmycin bioprecursors by cytochrome P450 enzymes provides an opportunity to treat drug-resistant breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4541. doi:10.1158/1538-7445.AM2015-4541
-
Solid-Phase Synthesis of Duocarmycin Analogues and the Effect of C‑Terminal Substitution on Biological Activity
2015Co-Authors: Michael J. Stephenson, Lesley A. Howell, Keith R. Fox, Claire Adcock, Jenny Kingston, Helen M. Sheldrake, Klaus Pors, Stephen Paul Collingwood, Maria A. O’connell, Mark SearceyAbstract:The Duocarmycins are potent antitumor agents with potential for use in the development of antibody–drug conjugates (ADCs) as well as being clinical candidates in their own right. In this article, we describe the synthesis of a Duocarmycin monomer (DSA) that is suitably protected for utilization in solid-phase synthesis. The synthesis was performed on a large scale, and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers; its application to solid-phase synthesis methodology gave a series of monomeric and extended Duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to that in previous reports for both the monomeric and extended compounds. Substitution at the C-terminus of Duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine, but this had no beneficial effects on biological activity
-
abstract 2224 re engineering of the Duocarmycin structural architecture enables tumour selective cyp2w1 mediated drug activation in human colon cancer xenografts
Cancer Research, 2013Co-Authors: Klaus Pors, Helen M. Sheldrake, Mark Searcey, Steven D. Shnyder, Paul M. Loadman, Mark Sutherland, Inger Johansson, Souren Mkrtchian, Sandra Travica, Magnus IngelmansundbergAbstract:There is now growing evidence that CYP1A1, 1B1, 2J2, 2S1 and 2W1 are over-expressed in many human tumour types. The ultrapotent Duocarmycins are ideal candidates for bioprecursor drug development and we have demonstrated that these can be re-engineered into derivatives selectively activated by CYP1A1 in vitro and in vivo. 1 , 2 In the present study, we have focussed on CYP2W1 as a potential therapeutic target. CYP2W1 is detected in 30% of colon cancers, while its protein expression in non-transformed adult tissues is absent or insignificant. 3 We have presented results indicating that the immunohistochemically assessed level of CYP2W1 enzyme could fulfil the criteria for being a prognostic biomarker for stages II and III colorectal cancer. 4 Here we present data on furanoindole-based Duocarmycins that have the potential to be used as a chemical probe (e.g. ICT2726) to show CYP2W1 functional activity. We also report on indoline-based analogues that elicit potent antiproliferative activity after CYP2W1-mediated activation in cancer cells. Specifically, we have transfected human HEK293, Colo320 and SW480 cells to express CYP2W1 and shown that these suffer rapid loss of viability following treatment with two halogenated Duocarmycin bioprecursor compounds (ICT2705 and ICT2706) while no activity in mock-transfected cells was seen. Significantly, ICT2706 was shown to totally prevent tumour growth when administered to SCID mice bearing SW480-2W1 xenografts (dosed daily with 100 mg/kg for 8 days) but not the mock-transfected variant. Subsequent to this treatment, the tumours were extracted for further analysis. Using H2A.X phosphorylation as a marker for DNA damage, our data revealed a time-dependent increase in expression supporting CYP2W1-mediated activation of ICT2706 in vivo. Our findings reveal the opportunities in targeting CYP2W1 as a novel therapeutic approach in colon cancer chemotherapy. Citation Format: Klaus Pors, Sandra Travica, Paul M. Loadman, Steven D. Shnyder, Mark Sutherland, Helen M. Sheldrake, Mark Searcey, Inger Johansson, Souren Mkrtchian, Magnus IngelmanSundberg, Laurence H. Patterson. Re-engineering of the Duocarmycin structural architecture enables tumour-selective CYP2W1-mediated drug activation in human colon cancer xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2224. doi:10.1158/1538-7445.AM2013-2224
