Medicinal Chemistry - Volume 11, Issue 4, 2015

A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.

Nonplanar 9,10-dihydroacridines were synthesized as promising C2 symmetric molecular scaffolds as inhibitors of the transmembrane efflux pump ABCB1. Within the series structure-activity relationships are discussed revealing the importance of hydrogen bond acceptor functions. A selectivity of ABCB1 inhibition is demonstrated for selected candidates and a bioanalytical study proved nontoxicity as well as missing ABCB1 substrate properties. The results encourage to further develop the promising class of ABCB1 inhibitors.

A library of twenty-five derivatives of 2-substituted quinazolin-4(3H)-ones 1-25 was synthesized and evaluated against phosphodiesterase-I (PDE) and carbonic anhydrase-II (CA). Compounds 17 (IC50 = 210.7 ± 2.62 µM), 16 (IC50 = 301.6 ± 1.18 µM), and 13 (IC50 = 458.13 ± 3.60 µM), selectively exhibited PDE inhibition while compounds 22 (IC50 = 61.33 ± 2.38 µM), 1 (IC50 = 108.30 ± 0.93 µM), and 21 (IC50 = 191.93 ± 2.72 µM), discriminatingly exhibited CA inhibition as compared to standards EDTA (IC50 = 277.69 ± 2.52 µM) and acetazolamide (IC50 = 0.12 ± 0.03µM), for PDE and CA inhibitions, respectively. However, compound 15 was found to be active against both enzymes with the IC50 values 344.33 ± 4.32 µM and 20.94 ± 0.58 µM, for PDE and CA inhibitions, respectively. Remaining compounds were found to be inactive against both the enzymes. Structure-activity relationship studies are discussed herein.

A series of 1,3,6-triphenylpyrazolo[3,4-b]pyridin-4-one derivatives was designed, synthesized and evaluated for cytotoxic activity in A375 human melanoma and human erythroleukemia (HEL) cells. The new pyrazolopyridones displayed comparable activities to the antitumor compound etoposide. The inhibitory effect of compounds 17, 18, 27 and 32 against topoisomerase II-mediated cleavage activities was measured finding good correlation with the results obtained from MTS assay. Docking studies into bacterial topoisomerase II (DNA Gyrase), topoisomerase IIα and topoisomerase IIβ binding sites in the DNA binding interface were performed.

The intrinsic fluorescence of synthetic or natural porphyrins is regarded as an attractive characteristic exploited for assisting early cancer diagnosis and/or tumor localization. Single tumor cells circulating in the blood stream can be considered a major step in depicting dissemination of primary tumors, an event of clinical relevance for prognosis, staging or therapy monitoring of cancer. The third leading cause of cancer death in men is colorectal cancer and the hematogenous spreading of primary tumor cells is one of the main events in metastasis of this type of cancer. Hidden in the myriad of circulating blood cells, tumor cells need both a sensitive and affordable detection technique. 5- (3-methoxy)-4-methoxycarbonylphenyl)-10, 15, 20-tris-(4- methoxycarbonylphenyl) - 21, 23-H porphyne is a synthetic porphyrin with a noticeable preference of accumulation in peripheral blood mononuclear cells isolated from cancer patients as assessed by flow cytometry analysis. In addition, we found distinct accumulation of porphyrin depending on cancer type (cutaneous melanoma versus colorectal cancer). These data lead to the possibility of identifying circulating cells based on preferential accumulation of this new porphyrin in circulating tumor cells because, even accumulated in low percentage of cells the registered intensity of fluorescence was high. Selecting the genetic markers for circulating tumor cells is an option, but high costs and high level of know-how can be somewhat a hurdle for a rapid evaluation. Thus our approach with a new porphyrin can be developed in an accurate and innovative fast tracking method for circulating cancer cells, at least in colorectal cancer patients.

Isothioureas are a class of amphiphilic compounds carrying a highly basic isothiourea group of pKa ranging between 10 and 11. Hence, they exist in protonated (cation) form at physiological pH, a characteristic is of key importance for their pharmacological activity. Recently, we have found that a number of S-pentabromobenzylisothiourea derivatives show substantial cytotoxicity toward a variety of human glioblastoma, leukemia, and adenocarcinoma cell lines. Whereas there is a growing body of data on aliphatic and alkylaromatic isothioureas, little attention was given to this day to heterocyclic isotiourea derivatives. Here we report on the synthesis and pharmacological in vitro properties of 10 novel S-(benzimidazol-2-ylmethyl)- and S-(5,6-dichlorobenzimidazol-2-ylmethyl)isothiourea derivatives. The compounds were obtained by the condensation of the respective 2-chloromethyl benzimidazoles with various substituted N(N’)-thioureas. Besides the essential physicochemical characteristics (H-NMR, UV, elemental analysis) of the new compounds, their log P values, which are of key importance for in vivo drug distribution and interactions, were determined. Pharmacological (anticancer) activity of the compounds was evaluated based on their ability to induce apoptosis in exponentially growing cultures of the human acute myelogenous leukemia cell line KG-1; the apoptosis was assessed with a variety of flow cytometric methods. Of the novel compounds tested, the most potent apoptosis inducer in KG-1 cells was N-methyl-S- (5,6-dichloro-1H-benzimidazol-2-ylmethyl)isothiouronium chloride (ClBMMe).

We tested the antiproliferative activity and mechanism of the action of several novel aminoacridine derivatives. Six different cancer cell lines were used to evaluate the potential cytotoxic effect of eleven aminoacridine-based molecules. A standard MTT assay was used for cell bioavailability analysis. Additionally, the potential cytotoxic effect of the tested compounds on non-cancer cells was investigated in rat skeletal muscle myotubes (L6) and in bovine aortic smooth muscle cells. In order to investigate whether the DNA binding activity of tested compounds correlated with their cytotoxic effect, circular dichroism (CD) measurement and DNA T4 ligase assay were performed. Finally, the potential mutagenic activity of the lead compound 5 was investigated. The cytotoxic effect of compound 5 in cancer cells was obtained in lower concentrations than the well-known: 9- aminoacridine based drug, amsacrine. The lead compound binds to DNA, but in a different mode than the parent molecules. Additionally, compound 5 was not cytotoxic in the effective range of concentrations in non-cancer cells. In identical concentrations, the parent compound (9-aminoacridine) and amsacrine were extremely toxic for both types of these normal cells. Finally, based on CD measurement and T4 ligase assay, it was confirmed that 5 binds to DNA but in different from the parent compounds manner. Important to mention, that compound 5 might have increased mutagenic activity which must be verified in vivo. Based on these in vitro results, we conclude that 5 is a more potent and more selective antiprolifirative compound than amsacrine. Compound 5 was also more effective in HepG2 and P-12 cells. Thus, 5 is suitable for future in vivo biological evaluation and its structure might be used as a basis for developing novel anticancer drugs.

Lycium barbarum polysaccharide (LBP) has traditionally been used in Chinese medicine as a chief ingredient of Lycium barbarum (wolf berry/goji berry) for the treatment of various diseases with the symptoms of frequent drinking and urination. This study was conducted as a randomized, controlled clinical trial. A total of 67 patients with type 2 diabetes (30 in control group and 37 in LBP group) were enrolled in this prospective, randomized, double-blind study (administration at 300mg/day body weight). In order to observe the hypoglycemic and lipid-lowering activity of LBP in patients with type 2 diabetes after dinner, various tests were conducted between control and LBP intervention groups in 3 months. Although, the study had small sample size and short follow-up, significant findings were observed. The results of our study indicated a remarkable protective effect of LBP in patients with type 2 diabetes. Serum glucose was found to be significantly decreased and insulinogenic index increased during OMTT after 3 months administration of LBP. LBP also increased HDL levels in patients with type 2 diabetes. It showed more obvious hypoglycemic efficacy for those people who did not take any hypoglycemic medicine compared to patients taking hypoglycemic medicines. This study showed LBP to be a good potential treatment aided-agent for type 2 diabetes.

Therapeutic guidelines indicate prostacyclin as the first line of treatment in inflammation and vascular diseases. Prostacyclins prevent formation of the platelet plug involved in primary hemostasis by inhibiting platelet activation and, combined with thromboxane, are effective vasodilators in vascular damage. Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease II guidelines indicates prostacyclins; in particular, Iloprost, as the first therapeutic option for treating peripheral arterial disease. However, therapeutic efficacy of Iloprost has witnessed several drawbacks that have occurred in patients receiving repeated weekly administration of the drug by intravenous infusions. Adverse reactions arose under perfusion with Iloprost for 6 h and patient compliance was drastically decreased. Biomedical devices could provide a suitable alternative to overcome these drawbacks. In particular, elastomeric pumps, filled with Iloprost isotonic solution, could slowly release the drug, thus decreasing its side effects, representing a valid alternative to hospitalization of patients affected by peripheral arterial disease. However, the home therapy treatment of patients requires long-term stability of Iloprost in solution-loaded elastomeric pumps. The aim of this work was to investigate the long-term stability of Iloprost isotonic solution in biomedical devices using Turbiscan technology. Turbiscan Lab Expert (L’Union, France) predicts the long-term stability of suspensions, emulsions and colloidal formulations by measuring backscattering and transmission of particulates dispersed in solution. The formulations were evaluated by measuring the variation of physical-chemical properties of colloids and suspensions as a function of backscattering and transmission modifications. In addition, the release profile of Iloprost isotonic solution from the biomedical device was evaluated.

Glioblastoma Multiforme (GBM) is a highly fatal disease and new chemotherapeutic agents are desperately needed to treat GBM patients. With the aim of identifying new antiglioma agents we screened the UC DDC library for compounds structurally related to the antiglioma lead molecule compound 1 (SP-6-27) and clinically used compound 2 (Azixa). We identified imidazoquinoline analog 3 (S-94403) as initial hit from the first screen which included the different heterocyclic sets of 15 compounds. Based on the initial hit 3 (S-94403), a second search was performed to explore the structure activity relationship (SAR) study on imidazoquinolines. Our SAR revealed that a N-phenyl with EDGs/EWGs at C9 position, a methyl group at C7 position and an aryl or hetero-aryl groups at C2 position essential for the anticancer activity. These two consecutive screenings have identified the compounds S-94403 (IC50 = 0.625 µM) and S-98950 (IC50 = 1.04 µM) as the most potent imidazoquinoline-based antiglioma agents.

This work describes the synthesis of new series of compounds derived from methyl pyridyl- 2,4-dioxobutanoates that contain pyridine ring attached to substituted bioactive heterocyclic moieties in order to investigate their preliminary in vitro antibacterial and antifungal activities. The results revealed that most of the tested compounds exhibited significant activity against P. aeruginosa. and E. coli. They also displayed considerable activity against S. aureus and B. subtilis. On the other hand, the compounds displayed moderate antifungal activity.