Novel TDP1 Inhibitors: Disubstituted Thiazolidine-2,4-Diones Containing Monoterpene Moieties.

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. The screening revealed some active compounds with IC50 values less than 5 µM. Interestingly, compounds 20d and 21d were the most active, with IC50 values in the submicromolar concentration range. None of the compounds showed cytotoxicity against HCT-116 (colon carcinoma) and MRC-5 (human lung fibroblasts) cell lines in the 1-100 µM concentration range. Finally, this class of compounds did not sensitize cancer cells to the cytotoxic effect of topotecan

New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising therapeutic target in cancer therapy. Combination chemotherapy using Tdp1 inhibitors as a component can potentially improve therapeutic response to many chemotherapeutic regimes. A new set of usnic acid derivatives with hydrazonothiazole pharmacophore moieties were synthesized and evaluated as Tdp1 inhibitors. Most of these compounds were found to be potent inhibitors with IC50 values in the low nanomolar range. The activity of the compounds was verified by binding experiments and supported by molecular modeling. The ability of the most effective inhibitors, used at non-toxic concentrations, to sensitize tumors to the anticancer drug topotecan was also demonstrated. The order of administration of the inhibitor and topotecan on their synergistic effect was studied, suggesting that prior or simultaneous introduction of the inhibitor with topotecan is the most effective

Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents

It is now established that the thieno[2,3-b]pyridines are a potent class of antiproliferatives. One of the main issues encountered for their clinical application is their low water solubility. In order to improve this, two strategies were pursued. First, a morpholine moiety was tethered to the molecular scaffold by substituting the sulphur atom with nitrogen, resulting in a 1H-pyrrolo[2,3-b]pyridine core structure. The water solubility was increased by three orders of magnitude, from 1.2 µg/mL (1-thieno[2,3-b]pyridine) to 1.3 mg/mL (3-pyrrolo[2,3-b]pyridine), however, it was only marginally active against cancer cells. The second strategy involved loading a very potent thieno[2,3-b]pyridine derivative (2) into a cholesteryl-poly(allylamine) polymer matrix for water solubilisation. Suppression of human pancreatic adenocarcinoma (BxPC-3) viability was observed to an IC50 value of 0.5 µg/mL (1.30 µM) in conjunction with the polymer, which is a five-fold (×5) increase in potency as compared to the free drug alone, demonstrating the utility of this formulation approach

Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs.

Cancer chemotherapy sensitizers hold the key to maximizing the potential of standard anticancer treatments. We have a long-standing interest in developing and validating inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) as chemosensitizers for topoisomerase I poisons such as topotecan. Herein, by using thieno[2,3-b]pyridines, a class of TDP1 inhibitors, we showed that the inhibition of TDP1 can restore sensitivity to topotecan, results that are supported by TDP1 knockout cell experiments using CRISPR/Cas9. However, we also found that the restored sensitivity towards topoisomerase I inhibitors is likely regulated by multiple complementary DNA repair pathways. Our results showed that one of these pathways is likely modulated by PARP1, although it is also possible that other redundant and partially overlapping pathways may be involved in the DNA repair process. Our work thus raises the prospect of targeting multiple DNA repair pathways to increase the sensitivity to topoisomerase I inhibitors

Are the metal identity and stoichiometry of metal complexes important for colchicine site binding and inhibition of tubulin polymerization?

Quite recently we discovered that copper(II) complexes with isomeric morpholine-thiosemicarbazone (morph-TSCs) hybrid ligands show good cytotoxicity in cancer cells and that the molecular target responsible for this activity might be..

New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

Six morpholine-(iso)­thiosemicarbazone hybrids HL1–HL6 and their Cu­(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu­(II) complexes [Cu­(L1–6)­Cl] (1–6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu­(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2–5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2–5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction

Defining Known Drug Space Using DFT.

A density functional theory (DFT) study was performed on a collection of clinically approved drugs, or Known Drug Space (KDS), to determine the statistical distribution of four properties: dipole moment (DM), polarisability (POL), ionisation potential (IP) and electron affinity (EA). The DM and POL are linked to cell permeability of drugs whereas IP and EA reflect their redox stability thus ease of metabolism. A benchmarking exercise showed a good correlation between experimental values and their predicted counterparts. It was found that KDS occupies the volume of chemical space defined by: DM≤10 D, POL≤68 Å3, IP 6.0–9.0 V and EA−1.5–2.0 eV. Only 16 % of the drugs are outside one or more of these parameters. Three categories based on known oral absorption and bioavailability (low/medium/high) were established and compared. Predominately, drugs designated as ‘low’ were found outside the established parameters. The properties were compared with mainstream molecular descriptors and a strong correlation was seen for POL to MW (r2=0.899), which can explain the success of the latter since POL reflects the ability of molecules to interact with polar and non-polar environments such as water and interior of a membrane

Acoustic abundance estimates of the Icelandic stock of capelin, October 1978 - January 1980.

During the period October 1978 - January 1980 several estimates of the size and yearclass composition of the Icelandic capelin stock were obtained by the acoustic method. Surveying was carried out in October 1978, February, JulyAugust, late September and October 1979 and in January in 1980. No estimates are presented for 0-group capelin since the surveys did not cover all its distribution and it has been shown that, compared to older yearclasses, it lS underrepresented in the samples. Similar problems were encountered with I-group capelin, but to a lesser degree. Seasonal variations in stock size estimates are described and discussed. As yet there is lack of comparative data from the summer- early autumn period. The various estimates obtained in October and January-February, are consistent and have been used for management purposes