Alexander S. Tikhomirov

Synthesis and Characterization of 4,11-Diaminoanthra[2,3-b]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD+/NADH Ratio and SIRT1

A series of new 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives with different side chains were synthesized. Selected 2-unsubstituted derivatives 11-14 showed high antiproliferative potency on a panel of mammalian tumor cell lines including multidrug resistance variants. Compounds 11-14 utilized multiple mechanisms of cytotoxicity including inhibition of Top1/Top2-mediated DNA relaxation, reduced NAD(+)/NADH ratio through tNOX inhibition, suppression of a NAD(+)-dependent sirtuin 1 (SIRT1) deacetylase activity, and activation of caspase-mediated apoptosis. Here, for the first time, we report that tumor-associated NADH oxidase (tNOX) and SIRT1 are important cellular targets of antitumor anthracene-9,10-diones.

Heterocyclic analogs of 5,12-naphthacene-quinone. 11*. A new method for preparing 4,11-dimethoxyanthra[2,3-b]furan-5,10-dione

A new method was developed for the synthesis of 4,11-dimethoxyanthra[2,3-b]furan-5,10-dione and some of its previously unknown derivatives. The method was based on heterocyclization of 2-(3-halo-anthraquinon-2-yl)formylacetic acid derivatives by the action of bases, leading to methyl 4,11-dimethoxy-5,10-dioxoanthra[2,3-b]furan-3-carboxylate. Subsequent acid hydrolysis of the ester group and decarboxylation of the obtained acid gave 4,11-dimethoxyanthra[2,3-b]furan-5,10-dione. The low yield of the target compound was probably due to heterocycle instability in the 5,10-dioxo-anthra[2,3-b]furan-3-carboxylic acid derivatives in basic medium.

Advances in the Discovery of Anthraquinone-Based Anticancer Agents

BACKGROUND The anthracene-9,10-dione (anthraquinone) derivatives represent an exceptionally valuable class in anticancer drug development. An outstanding antitumor potency of the anthracycline antibiotics attracted the attention of medicinal chemists since the discovery of these chemotypes. The prominent anthraquinone-based drugs doxorubicin, mitoxantrone as well as more recent epirubicin, idarubicin, and valrubicin are successfully used in chemotherapy of hematological malignancies and solid tumors. The anthraquinone core remains a promising scaffold for the search of new optimized drug candidates. OBJECTIVE In this study, we analyze the progress in discovery and development of antitumor anthracene- 9,10-diones based on patent and journal publications in 2008-2017. The main goal is to dissect novel chemotypes of anthraquinone derivatives; other important issues such as the success in bioconjugate chemistry of anthraquinone containing agents as well as the patents on new applications of anthracyclines are beyond the scope of this review. CONCLUSION A number of newly discovered natural products, the perspective directions for chemical modifications to optimize the anticancer properties, and novel intracellular targets demonstrate that anthracene- 9,10-diones deserve further in-depth investigation as an important source of drug candidates.

Development and pharmaceutical evaluation of the anticancer Anthrafuran/Cavitron complex, a prototypic parenteral drug formulation

&NA; To improve the water solubility of the anticancer drug candidate LCTA‐2034 (A1), we investigated the formation of complexes of this anthrax[2,3‐b]furan congener with the solubilizing 2‐hydroxypropyl derivative of &bgr;‐cyclodextrin HP‐&bgr;CD (Cavitron®). The interaction of A1 with HP‐&bgr;CD resulted in the inclusion complex A1/HP‐&bgr;CD in 1:1 stoichiometry. The A1/HP‐&bgr;CD complex was used to develop a prototype of a lyophilised drug formulation with enhanced (>10‐fold) aqueous solubility than A1 and a long‐term stability. The use of HP‐&bgr;CD decreased the acute toxicity of A1 by >30%. The A1/HP‐&bgr;CD drug formulation as well as A1 in equal doses (5 × 30 mg/kg) to increase the lifespan by up to 140% for mice with i.p. transplanted P388 leukaemia. Furthermore, the A1/HP‐&bgr;CD formulation demonstrated a significant and reliable antitumor efficacy in a P388/ADR drug resistant leukaemia and B16/F10 melanoma, proving a perspective of investigations of toxicology, biodistribution and pharmacokinetics. Graphical abstract Figure. No caption available.

Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives

A series of 4-aminomethyl derivatives of heliomycin 1 was prepared using the Mannich reaction. The modification significantly improved aqueous solubility of the initially poorly soluble antibiotic. Testing the antiproliferative efficacy revealed a potent activity of heliomycin as well as its new derivatives on a panel of mammalian tumor cells including drug resistant variants. In contrast to 1 the new derivatives 7a, 7l, 7p generated a high level of ROS associated with induction of apoptosis in T24 bladder cancer cells. Introduction of 4-aminomethyl moiety increased the affinity to DNA and the ability to inhibit topoisomerase 1 making 7p the most promising candidate for further preclinical evaluation. Thus, aminomethylation is the first-in-class successful transformation of the antibiotic 1 resulting in an improved water solubility of derivatives and promising properties in search of novel anticancer drug candidates.

Heterocyclic Analogs of 5,12-Naphthacenequinone 14 * . Synthesis of naphtho[2,3- f ]indole-3-carboxylic Acid Derivatives

3-carboxylate by using vicarious substitution of hydrogen, followed by intramolecular reductive heterocyclization. Some chemical properties of the target compound were characterized. As observed for the first time in the series of linear hetaryl-fused anthraquinones, the alkylation of hydroxy groups in naphtho[2,3-f]indole-5,10-diones gave not only 4,11-dialkoxy derivatives, but also the isomeric 5,10-dialkoxy derivatives of naphtho[2,3-f]indole-4,11-dione.

Semi-Synthetic Derivatives of Heliomycin with an Antiproliferative Potency

BACKGROUND Heliomycin (resistomycin), an antibiotic with broad spectra of biological activities including antimicrobial, antifungal, antiviral, and antiproliferative. However, an extremely low solubility in aqueous media and in the majority of organic solvents limits its practical application. OBJECTIVE Due to a high practical potential of heliomycin, new routes of structural modification are strongly required to improve its solubility. CONCLUSION The patent claims a series of 4-aminomethyl derivatives of heliomycin as well as a pharmaceutical composition based on it. Application of Mannich aminomethylation allowed to diversify the structure of initial antibiotic and to obtain the derivatives with significantly improved water solubility and a potent antiproliferative efficacy.

Tri-armed ligands of G-quadruplex on heteroarene-fused anthraquinone scaffolds: Design, synthesis and pre-screening of biological properties

Here, a combined molecular modelling methodology was used to identify the binding mode of 4,11-bis((2-guanidinoethyl)amino)anthra[2,3-b]thiophene-5,10-dione (1), a previously reported G4 ligand. After calculating the optimal interaction parameters 1 with the target, two series of tri-armed ligands based on furan- or thiophene-fused anthraquinone scaffolds were designed and synthesized. The new compounds bearing an additional side chain at the 2-position of the heterocycle and the 4,11-side chains with different spacer lengths and structures of terminal groups demonstrated much stronger affinity for telomeric G4 (4-15 times) versus the parental ligand. Moreover, the specificity to the quadruplex over duplex DNA was significantly improved (up to 75 times) when the 3-guanidinopropyl side chain was introduced at the 2-position of the heterocycle ring. All tri-armed ligands demonstrated modest antiproliferative potency, which is likely due to low intracellular penetration. Nevertheless, this work shows how computer-aided rational design of new potent compounds can be used for targeted anticancer therapy.