Non-Phosphorus Lipids As New Antitumor Drug Prototypes

Russian Journal of Bioorganic Chemistry - The main classes of antitumor drugs (antimetabolites, anthracyclines, taxanes, and alkylating agents) act via DNA damage, inhibit DNA synthesis, and/or...     

The Change in the Linear Energy Transfer of a Clinical Proton Beam in the Presence of Gold Nanoparticles

Biophysics - Gold nanoparticles are promising radiosensitizers for proton radiotherapy. However, the physical mechanisms of gold nanoparticles radiosensitization remain unclear. In the present...     

Complexes of antiparallel telomeric G-quadruplex d(TTAGGG)4 with carboxymethyl tetracationic porphyrins

Porphyrins are a chemical class that is widely used in drug design. Cationic porphyrins may bind to DNA guanine quadruplexes. We report the parameters of the binding of 5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium) porphyrin (P1) and 5,10,15,20-tetrakis(N-etoxycarbonylmethyl-4-pyridinium) porphyrin (P2) to antiparallel telomeric G-quadruplex formed by d(TTAGGG)₄ sequence (TelQ). The binding constants (K _i ) and the number of binding sites (N _j ) were determined from absorption isotherms generated from the absorption spectra of complexes of P1 and P2 with TelQ. Compound P1 demonstrated a high affinity to TelQ (K _i = (40 ± 6) × 10⁶ M^?1, N ₁ = 1; K ₂ = (5.4 ± 0.4) × 10⁶ M^?1, N ₂ = 2). In contrast, the binding constants of P2-TelQ complexes (K ₁ = (3.1 ± 0.2) × 10⁶ M^?1, N ₁ = 1; K ₂ = (1.2 ± 0.2) × 10⁶ M^?1, N ₂ = 2) were one order of magnitude smaller than the corresponding values for P2-TelQ complexes. Measurements of the quantum yield and fluorescence lifetime of the drug’s TelQ complexes revealed two types of binding sites for P1 and P2 on the quadruplex oligonucleotide. We concluded that strong complexes can result from the interaction of the porphyrins with TTA loops whereas the weaker complexes are formed with G-quartets. The altered TelQ conformation detected by the circular dichroism spectra of P1-TelQ complexes can be explained by the disruption of the G-quartet. We conclude that peripheral carboxy groups contribute to the high affinity of P1 for the antiparallel telomeric G-quadruplex.     

Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinase

The first published synthesis and characterization of a purine-scaffold library of hsp90 inhibitors is presented. The purine-scaffold represents a platform for the creation of easily synthesizable and derivatizable soluble molecules that are amenable for oral administration. The most active compound of the series (71) exhibits binding to hsp90 comparable to the natural product derivative 17AAG that is now in Phase I clinical trial as a cancer therapeutic. Induces the degradation of Her2 tyrosine kinase and arrests the MCF-7 breast cancer cell line at low micromolar concentrations (IC50=2 microM).     

Multidrug-resistant tumor cells with decreased malignancy: a role for integrin alphavbeta3

We studied whether acquisition of multidrug resistance (MDR) by tumor cells can alter their integrin profile and malignant behavior. Hamster fibroblast cell line HET-SR-2SC-LNM was selected for MDR, yielding the 2SC/20 subline. Compared with the parental cells, the 2SC/20 subline weakly adhered to denatured collagen (dCol) which correlated with decreased expression of alphavbeta3, a dCol receptor. Importantly, 2SC/20 subline demonstrated significantly decreased activity of collagenase MMP-2, lower ability to invade Matrigel, and attenuated metastasis in syngeneic animals. We provide evidence for the first time that selection for MDR can be associated with down-regulation of alphavbeta3 integrin, supporting our recent proof of the pro-apoptotic role of this integrin (Oncogene 20 (2001) 4710). Lack of alphavbeta3 expression may link cell survival under toxic conditions with decreased malignancy of the resulting drug resistant tumor.     

Anthracycline antibiotics and their derivatives,inhibitors of topoisomerase I

The relationship between the structure of new semisynthetic derivatives of doxorubicin, daunorubicin, and carminomycin and their ability to inhibit topoisomerase I were studied. The new derivatives inhibit the activity of topoisomerase I at low concentrations, induce the death of K-562 leukemia cells in culture, and produce an antitumor effect in experimental animals bearing P388 leukemia.     

Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b]thiophene-5,10-diones,novel analogues of antitumor anthracene-9,10-diones

We developed the synthesis of a series of thiophene-fused tetracyclic analogues of the antitumor drug ametantrone. The reactions included nucleophilic substitution of methoxy groups in 4,11-dimethoxyanthra[2,3-b]thiophene-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b]thiophene-5,10-dione in good yields. Several compounds showed marked antiproliferative potency against doxorubicin-selected, P-glycoprotein-expressing tumor cells and p53^?/? cells. The cytotoxicity of some novel compounds for P-glycoprotein-positive cells is highly dependent on N-substituent at the terminal amino group of ethylenediamine moiety. The cytotoxic potency of selected compounds correlated with their ability to attenuate the functions of topoisomerase I and telomerase, strongly suggesting that these enzymes are the major targets of antitumor activity of anthra[2,3-b]thiophene-5,10-dione derivatives.     

Polymethylene derivatives of nucleic bases with ω-functional groups: VII. Cytotoxicity in the series of <Emphasis Type="Italic">N</Emphasis>-(2-oxocyclohexyl)-ω-oxoalkyl-substituted purines and pyrimidines

New polymethylene derivatives of the nucleic bases with β-diketo function in the ω-position have been synthesized by alkylation of uracil, thymine, cytosine, hypoxanthine, adenine, and N ²-isobutyryl guanine with 2-(ω-chloroalkanoyl)cyclohexanones. The physicochemical characteristics of compounds synthesized and their effect on tumor K562 and HCT116 cell lines have been studied.     

Synthesis and structure-activity relationship studies of 4,11-diaminonaphtho[2,3-f]indole-5,10-diones

We describe the synthesis of derivatives of 4,11-diaminonaphtho[2,3-f]indole-5,10-dione and their cytotoxicity for human tumor cells that express major determinants of altered anticancer drug response, the efflux pump P-glycoprotein, and non-functional p53. Nucleophilic substitution of methoxy groups in 4,11-dimethoxynaphtho[2,3-f]indole-5,10-dione with various ethylenediamines yielded the derivatives of 4,11-diaminonaphtho[2,3-f]indole-5,10-dione, the indole containing analogues of the antitumor agent ametantrone. The cytotoxicity of novel compounds for multidrug resistant, P-glycoprotein-expressing tumor cells is highly dependent on the N-substituent at the terminal amino group of the ethylenediamine moiety. Whereas p53 null colon carcinoma cells were less sensitive to the reference drug doxorubicin than their counterparts with wild type p53, the majority of novel naphthoindole derivatives were equally potent for both cell lines, regardless of the p53 status.     

Pim family of protein kinases: Structure,functions, and roles in hematopoietic malignancies

Phosphorylation is the universal regulatory mechanism of key physiological processes, such as development, cell differentiation, proliferation, survival, and malignant transformation. The review considers serine/threonine protein kinases of the Pim (proviral integration of Moloney virus) family, which were initially discovered in experimental lymphomas. Data on the gene structure, evolution, functions, and substrates of Pim protein kinases are provided. The role in the biology of hematopoietic malignancies is discussed for Pim-1 as the major isoform. Pim-1 is a proproliferative and prosurvival protein kinase. Pim-1 is constitutively active owing to autophosphorylation, and its downstream partners positively regulate the cell cycle. Pim-1 cooperates with the c-Myc oncoprotein in leukemogenesis and, like the Akt protein kinase, prevents cell death. Thus, Pim kinases are regarded as new therapeutic targets. An original test system for a phenotypic screening of Pim inhibitors is presented. In this test system, the growth of a genetically engineered Escherichia coli strain in the presence of kanamycin depends on the phosphorylation of aminoglycoside 3′-phosphotransferase VIII by Pim-1, and pharmacological inhibition of this phosphorylation increases bacterial cell lysis.