The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Dale L Boger - One of the best experts on this subject based on the ideXlab platform.
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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.
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Asymmetric Synthesis of a CBI-Based Cyclic N‑Acyl O‑Amino Phenol Duocarmycin Prodrug
2015Co-Authors: Mika Uematsu, Dale L BogerAbstract:A short, asymmetric synthesis of a cyclic N-acyl O-amino phenol duocarmycin prodrug subject to reductive activation based on the simplified 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) DNA Alkylation subunit is described. A key element of the approach entailed treatment of iodo-epoxide 7, prepared by N-Alkylation of 6 with (S)-glycidal 3-nosylate, with EtMgBr at room temperature to directly provide the optically pure alcohol 8 in 78% yield (99% ee) derived from an effective metal–halogen exchange and subsequent regioselective intramolecular 6-endo-tet cyclization. Following O-debenzylation, introduction of a protected N-methylhydroxamic acid, direct trannannular spirocyclization, and subsequent stereoelectronically controlled acid-catalyzed cleavage of the resulting cyclopropane (HCl), further improvements in a unique intramolecular cyclization with N–O bond formation originally introduced for formation of the reductively labile prodrug functionality are detailed
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asymmetric synthesis of a cbi based cyclic n acyl o amino phenol duocarmycin prodrug
Journal of Organic Chemistry, 2014Co-Authors: Mika Uematsu, Dale L BogerAbstract:A short, asymmetric synthesis of a cyclic N-acyl O-amino phenol duocarmycin prodrug subject to reductive activation based on the simplified 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) DNA Alkylation subunit is described. A key element of the approach entailed treatment of iodo-epoxide 7, prepared by N-Alkylation of 6 with (S)-glycidal 3-nosylate, with EtMgBr at room temperature to directly provide the optically pure alcohol 8 in 78% yield (99% ee) derived from an effective metal–halogen exchange and subsequent regioselective intramolecular 6-endo-tet cyclization. Following O-debenzylation, introduction of a protected N-methylhydroxamic acid, direct trannannular spirocyclization, and subsequent stereoelectronically controlled acid-catalyzed cleavage of the resulting cyclopropane (HCl), further improvements in a unique intramolecular cyclization with N–O bond formation originally introduced for formation of the reductively labile prodrug functionality are detailed.
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a fundamental relationship between hydrophobic properties and biological activity for the duocarmycin class of DNA alkylating antitumor drugs hydrophobic binding driven bonding
Journal of Medicinal Chemistry, 2013Co-Authors: Amanda L Wolfe, Katharine K Duncan, James P Lajiness, Kaicheng Zhu, Adam S Duerfeldt, Dale L BogerAbstract:Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA that feature the incorporation of ethylene glycol units (n = 1–5) into the methoxy substituents of the trimethoxyindole subunit are described. These derivatives exhibit progressively increasing water solubility along with progressive decreases in cell growth inhibitory activity and DNA Alkylation efficiency with the incremental ethylene glycol unit incorporations. Linear relationships of cLogP with −log IC50 for cell growth inhibition and −log AE (AE = cell-free DNA Alkylation efficiency) were observed, with the cLogP values spanning the productive range of 2.5–0.49 and the −log IC50 values spanning the range of 11.2–6.4, representing IC50 values that vary by a factor of 105 (0.008 to 370 nM). The results quantify the fundamental role played by the hydrophobic character of the compound in the expression of the biological activity of members in this class (driving the intrinsically reversible DNA Alkylation reaction) and define...
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A Fundamental Relationship between Hydrophobic Properties and Biological Activity for the Duocarmycin Class of DNA-Alkylating Antitumor Drugs: Hydrophobic-Binding-Driven Bonding
2013Co-Authors: Amanda L. Wolfe, Katharine K Duncan, James P Lajiness, Kaicheng Zhu, Adam S Duerfeldt, Dale L BogerAbstract:Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA that feature the incorporation of ethylene glycol units (n = 1–5) into the methoxy substituents of the trimethoxyindole subunit are described. These derivatives exhibit progressively increasing water solubility along with progressive decreases in cell growth inhibitory activity and DNA Alkylation efficiency with the incremental ethylene glycol unit incorporations. Linear relationships of cLogP with −log IC50 for cell growth inhibition and −log AE (AE = cell-free DNA Alkylation efficiency) were observed, with the cLogP values spanning the productive range of 2.5–0.49 and the −log IC50 values spanning the range of 11.2–6.4, representing IC50 values that vary by a factor of 105 (0.008 to 370 nM). The results quantify the fundamental role played by the hydrophobic character of the compound in the expression of the biological activity of members in this class (driving the intrinsically reversible DNA Alkylation reaction) and define the stunning magnitude of its effect
Hiroshi Sugiyama - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the DNA Alkylation properties of a chlorambucil conjugated cyclic pyrrole imidazole polyamide
Chemistry: A European Journal, 2021Co-Authors: Yuki Hirose, Kaori Hashiya, Toshikazu Bando, Hiroshi SugiyamaAbstract:Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA Alkylation properties of the resulting cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher Alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the Alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
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DNA Alkylation of the runx binding sequence by cbi pi polyamide conjugates
Chemistry: A European Journal, 2020Co-Authors: Rina Maeda, Toshikazu Bando, Kaori Hashiya, Shinji Ito, Hiroshi SugiyamaAbstract:Many types of molecular targeted drugs that inhibit cancer growth by acting on specific molecules have been developed. The runt-related transcription factor (RUNX) family, which induces cancer development by binding to a specific DNA sequence, has attracted attention as a new target for cancer treatment. We have developed Chb-M ¢ , which targets the RUNX-binding sequence. Chb-M ¢ was developed by conjugating pyrrole-imidazole (PI) polyamides and chlorambucil as an anticancer agent. It was recently reported that Chb-M ¢ had a remarkable anticancer effect in vivo. In this study, to explore the possibility of an alternative structure, we designed a new series of CBI-PI polyamides, in which seco-CBI was applied as a DNA-alkylating agent. We examined the characteristics of the CBI-PI polyamides targeting the RUNX-binding sequence and found that these conjugates have great potential for cancer treatment.
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evaluation of the DNA Alkylation property of a chlorambucil conjugated cyclic pyrrole imidazole polyamide
Chemistry: A European Journal, 2020Co-Authors: Hiroshi Sugiyama, Yuki Hirose, Kaori Hashiya, Toshikazu BandoAbstract:Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA Alkylation properties of the cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher Alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2 . Subsequent HPLC analysis revealed that the Alkylation site of conjugate 3 , which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2 . These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
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sequence specific DNA Alkylation by tandem py im polyamide conjugates
Chemistry-an Asian Journal, 2014Co-Authors: Rhys Dylan Taylor, Toshikazu Bando, Kaori Hashiya, Yusuke Kawamoto, Hiroshi SugiyamaAbstract:Tandem N-methylpyrrole-N-methylimidazole (Py-Im) polyamides with good sequence-specific DNA-alkylating activities have been designed and synthesized. Three alkylating tandem Py-Im polyamides with different linkers, which each contained the same moiety for the recognition of a 10 bp DNA sequence, were evaluated for their reactivity and selectivity by DNA Alkylation, using high-resolution denaturing gel electrophoresis. All three conjugates displayed high reactivities for the target sequence. In particular, polyamide 1, which contained a β-alanine linker, displayed the most-selective sequence-specific Alkylation towards the target 10 bp DNA sequence. The tandem Py-Im polyamide conjugates displayed greater sequence-specific DNA Alkylation than conventional hairpin Py-Im polyamide conjugates (4 and 5). For further research, the design of tandem Py-Im polyamide conjugates could play an important role in targeting specific gene sequences.
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sequence specific DNA Alkylation targeting for kras codon 13 mutation by pyrrole imidazole polyamide seco cbi conjugates
Chemistry: A European Journal, 2014Co-Authors: Rhys Dylan Taylor, Kaori Hashiya, Toshikazu Bando, Yusuke Kawamoto, Sefan Asamitsu, Tomohiro Takenaka, Makoto Yamamoto, Hiroki Nagase, Hiroshi SugiyamaAbstract:Hairpin N-methylpyrrole-N-methylimidazole polyamide seco-CBI conjugates 2-6 were designed for synthesis by Fmoc solid-phase synthesis, and their DNA-alkylating activities against the Kras codon 13 mutation were compared by high-resolution denaturing gel electrophoresis with 225 base pair (bp) DNA fragments. Conjugate 5 had high reactivity towards the Kras codon 13 mutation site, with Alkylation occurring at the A of the sequence 5'-ACGTCACCA-3' (site 2), including minor 1 bp-mismatch Alkylation against wild type 5'-ACGCCACCA-3' (site 3). Conjugate 6, which differs from conjugate 5 by exchanging one Py unit with a β unit, showed high selectivity but only weakly alkylated the A of 5'-ACGTCACCA-3' (site 2). The hairpin polyamide seco-CBI conjugate 5 thus alkylates according to Dervan's pairing rule with the pairing recognition which β/β pair targets T-A and A-T pairs. SPR and a computer-minimized model suggest that 5 binds to the target sequence with high affinity in a hairpin conformation, allowing for efficient DNA Alkylation.
Toshikazu Bando - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the DNA Alkylation properties of a chlorambucil conjugated cyclic pyrrole imidazole polyamide
Chemistry: A European Journal, 2021Co-Authors: Yuki Hirose, Kaori Hashiya, Toshikazu Bando, Hiroshi SugiyamaAbstract:Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA Alkylation properties of the resulting cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher Alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the Alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
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DNA Alkylation of the runx binding sequence by cbi pi polyamide conjugates
Chemistry: A European Journal, 2020Co-Authors: Rina Maeda, Toshikazu Bando, Kaori Hashiya, Shinji Ito, Hiroshi SugiyamaAbstract:Many types of molecular targeted drugs that inhibit cancer growth by acting on specific molecules have been developed. The runt-related transcription factor (RUNX) family, which induces cancer development by binding to a specific DNA sequence, has attracted attention as a new target for cancer treatment. We have developed Chb-M ¢ , which targets the RUNX-binding sequence. Chb-M ¢ was developed by conjugating pyrrole-imidazole (PI) polyamides and chlorambucil as an anticancer agent. It was recently reported that Chb-M ¢ had a remarkable anticancer effect in vivo. In this study, to explore the possibility of an alternative structure, we designed a new series of CBI-PI polyamides, in which seco-CBI was applied as a DNA-alkylating agent. We examined the characteristics of the CBI-PI polyamides targeting the RUNX-binding sequence and found that these conjugates have great potential for cancer treatment.
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evaluation of the DNA Alkylation property of a chlorambucil conjugated cyclic pyrrole imidazole polyamide
Chemistry: A European Journal, 2020Co-Authors: Hiroshi Sugiyama, Yuki Hirose, Kaori Hashiya, Toshikazu BandoAbstract:Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA Alkylation properties of the cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher Alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2 . Subsequent HPLC analysis revealed that the Alkylation site of conjugate 3 , which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2 . These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
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sequence specific DNA Alkylation by tandem py im polyamide conjugates
Chemistry-an Asian Journal, 2014Co-Authors: Rhys Dylan Taylor, Toshikazu Bando, Kaori Hashiya, Yusuke Kawamoto, Hiroshi SugiyamaAbstract:Tandem N-methylpyrrole-N-methylimidazole (Py-Im) polyamides with good sequence-specific DNA-alkylating activities have been designed and synthesized. Three alkylating tandem Py-Im polyamides with different linkers, which each contained the same moiety for the recognition of a 10 bp DNA sequence, were evaluated for their reactivity and selectivity by DNA Alkylation, using high-resolution denaturing gel electrophoresis. All three conjugates displayed high reactivities for the target sequence. In particular, polyamide 1, which contained a β-alanine linker, displayed the most-selective sequence-specific Alkylation towards the target 10 bp DNA sequence. The tandem Py-Im polyamide conjugates displayed greater sequence-specific DNA Alkylation than conventional hairpin Py-Im polyamide conjugates (4 and 5). For further research, the design of tandem Py-Im polyamide conjugates could play an important role in targeting specific gene sequences.
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sequence specific DNA Alkylation targeting for kras codon 13 mutation by pyrrole imidazole polyamide seco cbi conjugates
Chemistry: A European Journal, 2014Co-Authors: Rhys Dylan Taylor, Kaori Hashiya, Toshikazu Bando, Yusuke Kawamoto, Sefan Asamitsu, Tomohiro Takenaka, Makoto Yamamoto, Hiroki Nagase, Hiroshi SugiyamaAbstract:Hairpin N-methylpyrrole-N-methylimidazole polyamide seco-CBI conjugates 2-6 were designed for synthesis by Fmoc solid-phase synthesis, and their DNA-alkylating activities against the Kras codon 13 mutation were compared by high-resolution denaturing gel electrophoresis with 225 base pair (bp) DNA fragments. Conjugate 5 had high reactivity towards the Kras codon 13 mutation site, with Alkylation occurring at the A of the sequence 5'-ACGTCACCA-3' (site 2), including minor 1 bp-mismatch Alkylation against wild type 5'-ACGCCACCA-3' (site 3). Conjugate 6, which differs from conjugate 5 by exchanging one Py unit with a β unit, showed high selectivity but only weakly alkylated the A of 5'-ACGTCACCA-3' (site 2). The hairpin polyamide seco-CBI conjugate 5 thus alkylates according to Dervan's pairing rule with the pairing recognition which β/β pair targets T-A and A-T pairs. SPR and a computer-minimized model suggest that 5 binds to the target sequence with high affinity in a hairpin conformation, allowing for efficient DNA Alkylation.
Hong Zang - One of the best experts on this subject based on the ideXlab platform.
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Noncovalent DNA Binding Drives DNA Alkylation by Leinamycin: Evidence That the Z,E-5-(Thiazol-4-yl)-penta-2,4-dienone Moiety of the Natural Product Serves as an Atypical DNA Intercalator
2016Co-Authors: Mostafa I. Fekry, Jozsef Szekely, Sanjay Dutta, Leonid Breydo, Hong ZangAbstract:Molecular recognition and chemical modification of DNA are important in medicinal chemistry, toxicology, and biotechnology. Historically, natural products have revealed many interesting and unexpected mechanisms for noncovalent DNA binding and covalent DNA modification. The studies reported here characterize the molecular mechanisms underlying the efficient Alkylation of duplex DNA by the Streptomyces-derived natural product leinamycin. Previous studies suggested that Alkylation of duplex DNA by activated leinamycin (2) is driven by noncovalent association of the natural product with the double helix. This is striking because leinamycin does not contain a classical noncovalent DNA-binding motif, such as an intercalating unit, a groove binder, or a polycation. The experiments described here provide evidence that leinamycin is an atypical DNA-intercalating agent. A competition binding assay involving daunomycin-mediated inhibition of DNA Alkylation by leinamycin provided evidence that activated leinamycin binds to duplex DNA with an apparent binding constant of approximately 4.3 ± 0.4 × 103 M–1. Activated leinamycin caused duplex unwinding and hydrodynamic changes in DNA-containing solutions that are indicative of DNA intercalation. Characterization of the reaction of activated leinamycin with palindromic duplexes containing 5′-CG and 5′-GC target sites, bulge-containing duplexes, and 5-methylcytosine-containing duplexes provided evidence regarding the orientation of leinamycin with respect to target guanine residues. The data allow construction of a model for the leinamycin–DNA complex suggesting how a modest DNA-binding constant combines with proper positioning of the natural product to drive efficient Alkylation of guanine residues in the major groove of duplex DNA
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Noncovalent DNA Binding Drives DNA Alkylation by Leinamycin: Evidence That the Z,E-5-(Thiazol-4-yl)-penta-2,4-dienone Moiety of the Natural Product Serves as an Atypical DNA Intercalator
Journal of the American Chemical Society, 2011Co-Authors: Mostafa I. Fekry, Jozsef Szekely, Sanjay Dutta, Leonid Breydo, Hong ZangAbstract:Molecular recognition and chemical modification of DNA are important in medicinal chemistry, toxicology, and biotechnology. Historically, natural products have revealed many interesting and unexpected mechanisms for noncovalent DNA binding and covalent DNA modification. The studies reported here characterize the molecular mechanisms underlying the efficient Alkylation of duplex DNA by the Streptomyces-derived natural product leinamycin. Previous studies suggested that Alkylation of duplex DNA by activated leinamycin (2) is driven by noncovalent association of the natural product with the double helix. This is striking because leinamycin does not contain a classical noncovalent DNA-binding motif, such as an intercalating unit, a groove binder, or a polycation. The experiments described here provide evidence that leinamycin is an atypical DNA-intercalating agent. A competition binding assay involving daunomycin-mediated inhibition of DNA Alkylation by leinamycin provided evidence that activated leinamycin b...
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DNA binding and Alkylation by the left half of azinomycin b
Biochemistry, 2000Co-Authors: Hong Zang, Kent S GatesAbstract:Azinomycin B (also known as carzinophilin A) contains two electrophilic functional groupsan epoxide and an aziridine residuethat react with nucleophilic sites in duplex DNA to form cross-links at 5‘-dGNT and 5‘-dGNC sequences. Although the aziridine residue of azinomycin is undoubtedly required for cross-link formation, analogues containing an intact epoxide group but no aziridine residue retain significant biological activity. Azinomycin epoxide analogues (e.g., 5 and 6) are of interest due to their potent biological activity and because there is evidence that azinomycin may decompose in vivo to yield such compounds. To investigate the chemical events underlying the toxicity of azinomycin epoxides, DNA binding and Alkylation by synthetic analogues of azinomycin B (6, 8, and 9) that comprise the naphthalene-containing “left half” of the antibiotic have been investigated. The epoxide-containing analogue of azinomycin (6) efficiently alkylates guanosine residues in duplex DNA. DNA Alkylation by 6 is facilit...
Kaori Hashiya - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the DNA Alkylation properties of a chlorambucil conjugated cyclic pyrrole imidazole polyamide
Chemistry: A European Journal, 2021Co-Authors: Yuki Hirose, Kaori Hashiya, Toshikazu Bando, Hiroshi SugiyamaAbstract:Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA Alkylation properties of the resulting cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher Alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the Alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
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DNA Alkylation of the runx binding sequence by cbi pi polyamide conjugates
Chemistry: A European Journal, 2020Co-Authors: Rina Maeda, Toshikazu Bando, Kaori Hashiya, Shinji Ito, Hiroshi SugiyamaAbstract:Many types of molecular targeted drugs that inhibit cancer growth by acting on specific molecules have been developed. The runt-related transcription factor (RUNX) family, which induces cancer development by binding to a specific DNA sequence, has attracted attention as a new target for cancer treatment. We have developed Chb-M ¢ , which targets the RUNX-binding sequence. Chb-M ¢ was developed by conjugating pyrrole-imidazole (PI) polyamides and chlorambucil as an anticancer agent. It was recently reported that Chb-M ¢ had a remarkable anticancer effect in vivo. In this study, to explore the possibility of an alternative structure, we designed a new series of CBI-PI polyamides, in which seco-CBI was applied as a DNA-alkylating agent. We examined the characteristics of the CBI-PI polyamides targeting the RUNX-binding sequence and found that these conjugates have great potential for cancer treatment.
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evaluation of the DNA Alkylation property of a chlorambucil conjugated cyclic pyrrole imidazole polyamide
Chemistry: A European Journal, 2020Co-Authors: Hiroshi Sugiyama, Yuki Hirose, Kaori Hashiya, Toshikazu BandoAbstract:Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA Alkylation properties of the cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher Alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2 . Subsequent HPLC analysis revealed that the Alkylation site of conjugate 3 , which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2 . These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
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sequence specific DNA Alkylation by tandem py im polyamide conjugates
Chemistry-an Asian Journal, 2014Co-Authors: Rhys Dylan Taylor, Toshikazu Bando, Kaori Hashiya, Yusuke Kawamoto, Hiroshi SugiyamaAbstract:Tandem N-methylpyrrole-N-methylimidazole (Py-Im) polyamides with good sequence-specific DNA-alkylating activities have been designed and synthesized. Three alkylating tandem Py-Im polyamides with different linkers, which each contained the same moiety for the recognition of a 10 bp DNA sequence, were evaluated for their reactivity and selectivity by DNA Alkylation, using high-resolution denaturing gel electrophoresis. All three conjugates displayed high reactivities for the target sequence. In particular, polyamide 1, which contained a β-alanine linker, displayed the most-selective sequence-specific Alkylation towards the target 10 bp DNA sequence. The tandem Py-Im polyamide conjugates displayed greater sequence-specific DNA Alkylation than conventional hairpin Py-Im polyamide conjugates (4 and 5). For further research, the design of tandem Py-Im polyamide conjugates could play an important role in targeting specific gene sequences.
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sequence specific DNA Alkylation targeting for kras codon 13 mutation by pyrrole imidazole polyamide seco cbi conjugates
Chemistry: A European Journal, 2014Co-Authors: Rhys Dylan Taylor, Kaori Hashiya, Toshikazu Bando, Yusuke Kawamoto, Sefan Asamitsu, Tomohiro Takenaka, Makoto Yamamoto, Hiroki Nagase, Hiroshi SugiyamaAbstract:Hairpin N-methylpyrrole-N-methylimidazole polyamide seco-CBI conjugates 2-6 were designed for synthesis by Fmoc solid-phase synthesis, and their DNA-alkylating activities against the Kras codon 13 mutation were compared by high-resolution denaturing gel electrophoresis with 225 base pair (bp) DNA fragments. Conjugate 5 had high reactivity towards the Kras codon 13 mutation site, with Alkylation occurring at the A of the sequence 5'-ACGTCACCA-3' (site 2), including minor 1 bp-mismatch Alkylation against wild type 5'-ACGCCACCA-3' (site 3). Conjugate 6, which differs from conjugate 5 by exchanging one Py unit with a β unit, showed high selectivity but only weakly alkylated the A of 5'-ACGTCACCA-3' (site 2). The hairpin polyamide seco-CBI conjugate 5 thus alkylates according to Dervan's pairing rule with the pairing recognition which β/β pair targets T-A and A-T pairs. SPR and a computer-minimized model suggest that 5 binds to the target sequence with high affinity in a hairpin conformation, allowing for efficient DNA Alkylation.