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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.

ABSTRACT: 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.

SUBMITTER: Chanda PB

PROVIDER: S-EPMC5052114 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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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.

Chanda Prem B PB Boyle Kristopher E KE Brody Daniel M DM Shukla Vyom V Boger Dale L DL

Bioorganic & medicinal chemistry 20160426 20

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. ...[more]

PMID: 27221071

Similar Datasets

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.

Project description: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.

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Synthesis and characterization of a cyclobutane duocarmycin derivative incorporating the 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (CbBI) alkylation subunit.

Project description:The synthesis of 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (17, CbBI), which contains a deep-seated fundamental structural modification in the CC-1065 and duocarmycin alkylation subunit consisting of the incorporation of a ring-expanded fused cyclobutane (vs cyclopropane), its chemical and structural characterization, and its incorporation into a key analogue of the natural products are detailed. The approach to the preparation of CbBI was based on a precedented (Ar-3' and Ar-5') but previously unknown Ar-4' spirocyclization of a phenol onto a tethered alkyl halide to form the desired cyclobutane. The conditions required for the implementation of the Ar-4' spirocyclization indicate that the entropy of activation substantially impacts the rate of reaction relative to that for the much more facile Ar-3' spirocyclization, while the higher enthalpy of activation slows the reaction relative to an Ar-5' spirocyclization. The characterization of the CbBI-based agents revealed their exceptional stability and exquisite reaction regioselectivity, and a single-crystal X-ray structure analysis of N-Boc-CbBI (13) revealed their structural origins. The reaction regioselectivity may be attributed to the stereoelectronic alignment of the two available cyclobutane bonds with the cyclohexadienone π-system, which resides in the bond that extends to the less substituted cyclobutane carbon for 13. The remarkable stability of N-Boc-CbBI (which is stable even at pH 1) relative to N-Boc-CBI containing a cyclopropane (t(1/2) = 133 h at pH 3) may be attributed to a combination of the increased extent of vinylogous amide conjugation, the nonoptimal geometric alignment of the cyclobutane with the activating cyclohexadienone, and the intrinsic but modestly lower strain energy (1.8 kcal/mol) of a cyclobutane versus a cyclopropane.

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Synthesis and evaluation of a series of C5'-substituted duocarmycin SA analogs.

Project description: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.

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Synthesis and evaluation of a thio analogue of duocarmycin SA.

Project description: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.

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Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin.

Project description: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 IC(50) 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, characterization, and evaluation of 34 that is incapable of the more conventional para-spirocyclization. Although 34 proved sufficiently stable for isolation and characterization, it displayed little stability in protic solvents (t(1/2) = 0.19 h at pH 3, t(1/2) = 0.20 h at pH 7), a pH-independent (H(+) independent) solvolysis rate profile at pH 3/4-7, and a much reduced cytotoxic potency, but a DNA alkylation selectivity and efficiency comparable to those of duocarmycin SA and iso-duocarmycin SA. The implications of these observations on the source of the DNA alkylation selectivity and catalysis for this class of natural products are discussed.

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Duocarmycin SA, a potent antitumor antibiotic, sensitizes glioblastoma cells to proton radiation.

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5-Benzoyl-2-(1H-indol-3-yl)-4-(4-methyl-phen-yl)-4,5-dihydro-furan-3-carbonitrile.

Project description:The furan ring in the title compound, C(27)H(20)N(2)O(2), adopts a twisted conformation about the sp(3)-sp(3) bond. The mol-ecular structure is stabilized by an intra-molecular C-H?O inter-action which generates an S(6) ring motif. The crystal packing is stabilized by N-H?O and C-H?O inter-actions generating centrosymmetric R(2) (2)(18) and C(6) chain motifs, respectively. A weak C-H?? inter-action is also observed.

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Gene expression profile of Duocarmycin SA-treated human AML cell lines in vitro

Project description:Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by the expansion of immature myeloid precursors and poor patient survival outcomes. As such there is a need for the evaluation of potential therapeutic candidates that can be used in combination with current treatment regimens to improve patient outcomes. In this study, we investigated the efficacy of DSA on AML cells in vitro and performed gene expression profile analysis of DSA-treated AML cells to identify genes that are regulated by DSA. Here we report DSA-induced differentially expressed genes and cellular pathways that are associated with the functional changes that are observed in DSA-treated AML cells. Our data provides, for the first time, DSA's unique gene signature and provides a mechanistic rationale for DSA-induced functional effects in AML cells.

2024-05-01 | GSE245161 | GEO

Chromomycin SA analogs from a marine-derived Streptomyces sp.

Project description:Two chromomycin SA analogs, chromomycin SA(3) and chromomycin SA(2), along with deacetylchromomycin A(3) and five previously reported chromomycin analogs were isolated from a marine-derived Streptomyces sp. The structures of the new compounds were determined by spectroscopic methods including 1D and 2D NMR techniques, HRMS and chemical methods. Chromomycin SA(3) and chromomycin SA(2) are the first naturally occuring chromomycin analogs with truncated side-chains. Biological evaluation of chromomycin analogs for cytotoxicity against two non-small cell lung cancer (NSCLC) cell-lines, A549 and HCC44, demonstrated a decrease in cytotoxicity for the truncated sides chain chromomycin analogs.

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Methyl 3-(2-chlorophenyl)-2-(1H-indol-3-ylmethyl)-5-[1-(4-methoxyphenyl)-4-oxo-3-phenylazetidin-2-yl]-4-nitropyr-rolidine-2-carboxylate.

Project description:In the mol-ecule of the title compound, C(37)H(33)ClN(4)O(6), the four-membered β-lactam ring is essentially planar and is oriented at dihedral angles of 30.0 (1), 76.3 (1) and 30.9 (1)° with respect to the methoxy-phenyl ring, the phenyl ring and the indole unit, respectively. The pyrrolidine ring adopts a twist conformation. Intra-molecular C-H⋯Cl and C-H⋯O hydrogen bonds result in the formation of two five- and one six-membered rings. In the crystal structure, inter-molecular C-H⋯O and N-H⋯O hydrogen bonds link the mol-ecules. A weak π⋯π inter-action between the pyrrole rings further stabilizes the structure, with a centroid-centroid distance of 3.806 (2) Å.

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