ABSTRACT
Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the prognosis of AML patients remains poor and there is a need for the evaluation of promising therapeutic candidates to treat the disease. The objective of this study was to evaluate the efficacy of duocarmycin Stable A (DSA) in AML cells in vitro. We hypothesized that DSA would induce DNA damage in the form of DNA double-strand breaks (DSBs) and exert cytotoxic effects on AML cells within the picomolar range. Human AML cell lines Molm-14 and HL-60 were used to perform 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), DNA DSBs, cell cycle, 5-ethynyl-2-deoxyuridine (EdU), colony formation unit (CFU), Annexin V, RNA sequencing and other assays described in this study. Our results showed that DSA induced DNA DSBs, induced cell cycle arrest at the G2M phase, reduced proliferation and increased apoptosis in AML cells. Additionally, RNA sequencing results showed that DSA regulates genes that are associated with cellular processes such as DNA repair, G2M checkpoint and apoptosis. These results suggest that DSA is efficacious in AML cells and is therefore a promising potential therapeutic candidate that can be further evaluated for the treatment of AML.
Subject(s)
Apoptosis , Cell Proliferation , Duocarmycins , Leukemia, Myeloid, Acute , Humans , Apoptosis/drug effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/metabolism , Cell Proliferation/drug effects , Duocarmycins/pharmacology , Cell Line, Tumor , DNA Breaks, Double-Stranded/drug effects , HL-60 Cells , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , DNA Damage/drug effectsABSTRACT
New treatment modalities for glioblastoma multiforme (GBM) are urgently needed. Proton therapy is considered one of the most effective forms of radiation therapy for GBM. DNA alkylating agents such as temozolomide (TMZ) are known to increase the radiosensitivity of GBM to photon radiation. TMZ is a fairly impotent agent, while duocarmycin SA (DSA) is an extremely potent cytotoxic agent capable of inducing a sequence-selective alkylation of duplex DNA. Here, the effects of sub-nM concentrations of DSA on the radiosensitivity of a human GBM cell line (U-138) to proton irradiation were examined. Radiation sensitivity was determined by viability, apoptosis, necrosis and clonogenic assays. DSA concentrations as low as 0.001â¯nM significantly sensitized U-138 cells to proton irradiation. DSA demonstrates synergistic cytotoxicity against GBM cells treated with proton radiation in vitro, which may represent a novel therapeutic alternative for the treatment of GBM.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Indoles/pharmacology , Radiation-Sensitizing Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Duocarmycins , Glioblastoma , Humans , Necrosis/chemically induced , Protons , Pyrroles/pharmacologyABSTRACT
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.
Subject(s)
Imidazoles/pharmacology , Indoles/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Duocarmycins , Imidazoles/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Mice , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , StereoisomerismABSTRACT
The evaluation of a comprehensive α-helix mimetic library for binding the gp41 NHR hydrophobic pocket recognizing an intramolecular CHR α-helix provided a detailed depiction of structural features required for binding and led to the discovery of small molecule inhibitors (K(i) 0.6-1.3 µM) that not only match or exceed the potency of those disclosed over the past decade, but that also exhibit effective activity in a cell-cell fusion assay (IC(50) 5-8 µM).
Subject(s)
Anti-HIV Agents/chemistry , Drug Discovery , HIV Envelope Protein gp41/metabolism , HIV Fusion Inhibitors/chemistry , Molecular Mimicry , Small Molecule Libraries/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Structure, SecondaryABSTRACT
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.
Subject(s)
Alkylating Agents/chemical synthesis , Alkylating Agents/pharmacology , Indoles/chemistry , Oxazoles/chemistry , Alkylating Agents/chemistry , Alkylation , Duocarmycins , Indoles/chemical synthesis , Indoles/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacologyABSTRACT
The discovery of N-substituted-pyridoindolines and their binding affinities at the 5-HT(2A), 5-HT(2C) and D(2) receptors, and in vivo efficacy as 5-HT(2A) antagonists is described. The structure-activity relationship of a series of core tetracyclic derivatives with varying butyrophenone sidechains is also discussed. This study has led to the identification of potent, orally bioavailable 5-HT(2A)/D(2) receptor dual antagonists as potential atypical antipsychotics.