Substance P antagonists

Paclitaxel (Taxol^®) and docetaxel (Taxotere^®) are relatively new drugs used in cancer therapy and have shown great promise in the treatment of a variety of cancers. The taxane therapy, however, encounters two major problems. One problem is the low solubility of both paclitaxel and docetaxel; the second problem is multi-drug resistance. In the patent literature from 1995 - 1997 these two problems have been the main focus of research in the taxane field. Numerous taxoids have been disclosed with improved solubility, mainly by acylation of the C-2′ and C-7 hydroxyls. To reduce the multi-drug resistance susceptibility of the drugs, alterations on the taxane core and the phenylisoserine ring have been made. The patent literature also reports the discovery of new classes of compounds (epothilones, discodermolides, eleutherobins and sarcodictyins) that are structurally dissimilar from taxanes but have microtubule stabilisation activity and are potent inhibitors of cancer cells and paclitaxel-resistant cancer cells.     

Novel naphthalimide-benzoic acid conjugates as potential apoptosis-inducing agents: design, synthesis, and biological activity

A series of novel naphthalimide derivatives with 4‐[4‐(3,3‐diphenylallyl)piperazin‐1‐yl]benzoic acid as side chain were designed and synthesized. Their antitumor activities were evaluated against a variety of cancer cell lines in vitro. Preliminary results showed that most of the derivatives had cytotoxic activity comparable with that of amonafide, with IC₅₀ values of 10⁻⁶–10⁻⁵ m . Interestingly, compound 12e had the unique antitumor activity against MCF‐7 among the cancer cell lines tested. More importantly, flow cytometric analysis indicated that compared with amonafide, the target compounds could effectively induce G₂/M arrest and progress to apoptosis in HL‐60 cells after double staining with annexin V–FITC and propidium iodide. The present work provided a novel class of naphthalimide‐based derivatives with potential apoptosis‐inducing and improved antitumor activity for further optimization.     

Cytotoxic and trypanocidal activities of cinchona alkaloid derivatives

A series of 27 cinchona alkaloid derivatives ( 1f–w , 2a–e and 3a–d ) were investigated for their cytotoxic and trypanocidal activities using seven different cancer cell lines (KB, HeLa, MCF‐7, A‐549, Hep‐G2, U‐87 and HL‐60), two normal cell lines (HDF and CHO) and bloodstream forms of Trypanosoma brucei brucei, respectively. Four compounds ( 1u , 1w , 2e and 3d ) were identified with promising cytotoxic activity with 50% growth inhibition (GI₅₀) values below 10 μM. Two ( 2e and 3d ) of the four compounds also exhibited potent anti‐trypanosomal activity with GI₅₀ values of 0.3–0.4 μM. All four active compounds represented derivatives modified at their C‐9 hydroxy group. With respect to anti‐proliferative activity and selectivity, 2e (epi‐N‐quinidyl‐N′‐bis(3,5‐trifluoromethyl)phenylthiourea) proved to be the most promising derivative for both cancer cells and bloodstream forms of T. b. brucei. The cytotoxic activity of compounds 1u , 1w , 2e and 3d was attributed to their ability to induce apoptosis in cancer cells. The results demonstrate the potential of cinchona alkaloid derivatives as novel anti‐cancer and anti‐trypanosome drug candidates.     

Docetaxel in ovarian cancer

Docetaxel, a semisynthetic taxane, is a potent inhibitor of cell replication and, similar to paclitaxel, promotes in vitro assembly of stable microtubules and, therefore, prevents the depolymerisation process. Docetaxel has a higher affinity for the tubulin subunit and is associated with a 100-fold greater phosphorylation of BCL-2 inducing apoptosis. Docetaxel in combination with carboplatin demonstrates similar activity to paclitaxel/carboplatin in the upfront management of advanced ovarian cancer with less neurological, but greater haematological toxicity. This article reviews the rationale and indications for the use of docetaxel in ovarian cancer.     

Influence of dosing schedules on toxicity and antitumour effects of combined cisplatin and docetaxel treatment in mice

Objectives The combination of cisplatin and docetaxel shows a better cure rate against non‐small‐cell lung cancer than other drug combinations in clinical studies; however, severe myelosuppression and nephrotoxicity are dose‐limiting factors. The purpose of this study was to establish a suitable dosing schedule to reduce adverse effects and improve the antitumour effects. Methods Cisplatin and docetaxel were administered i.p. to male ICR mice simultaneously, or sequentially with either cisplatin or docetaxel first followed by the second drug 12 h later (docetaxel–cisplatin and cisplatin–docetaxel groups). Antitumour effects of these schedules were also tested in C57BL/6N mice bearing Lewis lung carcinomas. Key findings The simultaneous docetaxel/cisplatin group showed the lowest survival rate and the highest blood urea nitrogen (BUN) concentration. Cisplatin concentrations in the plasma and kidney were higher in the simultaneous dosing group than the sequential dosing groups. Antitumour effect was the greatest in the docetaxel–cisplatin group. Conclusions The docetaxel–cisplatin regimen inhibited tumour growth the best and reduced mortality and nephrotoxicity.     

Design,Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives as Anti‐inflammatory Agents against Lipopolysaccharide‐induced Acute Lung Injury in Rats

Quinazoline has been reported to exhibit multiple bioactivities. The aim of this study was to discover new quinazoline derivatives with preventive effect on lipopolysaccharide‐induced acute lung injury via anti‐inflammatory actions. Thirty‐three 4‐amino quinazolin derivatives were synthesized and screened for anti‐inflammatory activities in lipopolysaccharide‐induced macrophages. The most potent four compounds, 6h, 6m, 6p , and 6q , were shown dose‐dependent inhibition against lipopolysaccharide‐induced TNF‐α and IL‐6 release. Then, the preliminary structure–activity relationship and quantitative structure–activity relationship analyses were conducted. To further determine the effects of quinazolines on acute lung injury treatment, lipopolysaccharide‐induced acute lung injury model was employed. Male Sprague Dawley rats were pretreated with 6m or 6q before instillation of lipopolysaccharide. The results showed that 6m and 6q, especially 6q , obviously alleviated lung histopathological changes, inflammatory cells infiltration, and cytokines mRNA expression initiated by lipopolysaccharide. Taken together, this work suggests that 6m and 6q suppressed the lipopolysaccharide‐induced acute lung injury through inhibition of the inflammatory response in vivo and in vitro, indicating that quinazolines might serve as potential agents for the treatment of acute lung injury and deserve the continuing drug development and research.     

In-vitro antiproliferative activity of benzopyranone derivatives in comparison with standard chemotherapeutic drugs

The cytotoxic activities of five new benzopyranone derivatives containing basic amino side chain are described. Their cytotoxicities against ER(+) MCF‐7 and ER(–) MDA‐MB‐231 human breast cancer cell lines, and Ishikawa human endometrial cell line were determined after 72 h drug exposure employing CellTiter‐Glo assay at concentrations ranging from 0.01–1.0 × 10⁵ nM. The antiproliferative activities of these compounds were compared to tamoxifen (TAM), 4‐hydroxytamoxifen (4‐OHT, active metabolite of tamoxifen), and raloxifene (RAL). In‐vitro results indicated that compounds 9 , 10 , 12 , and 13 were more potent than TAM against the human breast cancer cell lines with IC₅₀ < 20 µM. The in‐silico structure–activity relationships of these compounds and their binding mode within the estrogen receptor (ER) binding site using AutoDock vina are discussed.     

Binding Orientations,QSAR, and Molecular Design of Thiophene Derivative Inhibitors

A theoretical study on binding orientations and quantitative structure–activity relationship of thiophene derivatives as inhibitors towards tubulin has been carried out by using the docking analysis and the comparative molecular field analysis. The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by docking study; and a 3D‐quantitative structure–activity relationship model showing significant statistical quality and satisfying predictive ability was established, in which the correlation coefficient (R²) and cross‐validation coefficient (q²) are 0.949 and 0.743, respectively. The same model was further applied to predict the pIC₅₀ values for nine congeneric compounds as external test set, and the predictive correlation coefficient reaches 0.929, thus the predictive ability of this 3D‐quantitative structure–activity relationship model can be further confirmed. Some key structural factors of the compounds responsible for cytotoxicity were discussed in detail. Based on these structural factors, three new compounds with higher activity have been designed, and their cytotoxicities were also predicted by the established 3D‐quantitative structure–activity relationship model from comparative molecular field analysis as well as the docking analysis. We hope these theoretical results can be confirmed by experimental work.     

Synthesis of new arylisoxazole–oxindole conjugates as potent antiproliferative agents

A new series of arylisoxazole–oxindole derivatives ( 6a–r ) were synthesized and evaluated for their antiproliferative activity against human cancer cell lines including non‐small cell lung (A549), cervical (HeLa), breast (MCF‐7), and prostate (DU‐145) cancer cell lines. The synthesized compounds ( 6a–r ) demonstrated excellent to moderate cytotoxicity with IC₅₀ values ranging from 0.82 to 3.69 μm . Some new compounds ( 6m–r ) exhibited profound cytotoxicity better or similar to positive control. More particularly, the compound 6q possesses donating substituent like methoxy group presented at 5‐position on D ring exhibited remarkable antiproliferative activity against A‐549 (lung cancer) with an IC₅₀ value 0.82 μm . Further studies to determine the mechanistic aspects of these conjugates are under progress.     

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

Phosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on our previous reported catecholic PDE4 inhibitors was built with a statistically significant cross‐validated coefficient (q²), conventional coefficient (r²), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles 16a–i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomolar IC₅₀ values and potential anti‐neuroinflammation activity in BV‐2 cells. Docking simulation of compound 16a in the PDE4 catalytic domain activity pocket revealed that compound 16a maybe assumed a “V‐shaped” conformation, extending the side chain to S‐pocket.     

Flavonoid compounds: a review of anticancer properties and interactions with cis‐diamminedichloroplatinum(II)

Flavonoid compounds, especially quercetin and genistein, have antitumor activity. These compounds are cytotoxic to cancer cells but have no or insignificant activity in normal cells. These beneficial properties prompted synthesis of flavonoid synthetic derivatives, e.g., flavopiridol; 5‐amino‐2,3‐fluorophenyl)‐6,8‐difluoro‐7‐methyl‐4H‐1‐benzopyran‐4‐one; B43‐genistein and EGF‐genistein). cis‐DDP (cis‐diamminedichloroplatinum(II)) is one of the most effective drugs used for chemotherapy, but its actions are limited by many side effects. Beneficial synergistic effects of flavonoids (e.g., quercetin, genistein, butein, tannic acid) and cis‐DDP were found in cis‐DDP‐sensitive and resistant cancer cells that resulted in a lower toxicity for cis‐DDP. Further studies focused on the synthesis of complexes of compounds belonging to different groups, e.g., cis‐bis(3‐aminoflavone)dichloroplatinum(II) where introduction of the flavone ligand altered the DNA‐binding properties of the complex as compared to cis‐DDP alone. The beneficial anticancer and antioxidant properties of flavonoids and their synthetic derivatives have prompted further research on the synergistic interactions of these compounds with routinely applied chemotherapeutic drugs, e.g. cis‐DDP. Drug Dev. Res. 63:200–211, 2004. © 2004 Wiley‐Liss, Inc.     

Elaborating on efficient anti-proliferation agents of cancer cells and anti-inflammatory-based N-bisphosphonic acids

Methylenebisphosponic acid tetraethyl ester ( 1 ) was added to 2‐azido‐ 7a–e and 2‐chloroquinoline‐3‐chalcones 10a–e in boiling sodium ethanolate solution to give, via Michael addition, tetrazolo[1,5‐a]quinoline‐ 8a–d , 13a and 2‐chloroquinoline‐based bisphosphonates 11a–d , 14a in E‐configuration. Further acid hydrolysis afforded the respective BP‐acid analogues E‐ 9a–d , 12a–d , 13b , and 14b in excellent yields. Anti‐tumor activity screening for the new BP‐acids at a dose of 10 µM utilizing 44 different human tumor cell lines representing breast, ovary, prostate, lung, and CNS cancer as well as leukemia and melanoma was carried out. Eight of ten tested compounds exhibited remarkable anti‐tumor activity against breast and prostate cancer, and a promising anti‐tumor sensitivity toward ovarian cancer and melanoma. Conversely, there was only scattered activity against leukemia and no noticeable action of these BP‐acids on CNS or lung cancer. Based on the prediction results (PASS program), anti‐inflammatory activity of the new acids was also determined in vivo, by the acute carrageenin induced paw edema in rats. Many of these compounds showed anti‐inflammatory properties at a dose of 50 mg/kg body weight.     

Nontoxic Suramin Treatments Enhance Docetaxel Activity in Chemotherapy-Pretreated Non-Small Cell Lung Xenograft Tumors

Purpose We reported that nontoxic suramin treatments enhance the activity of chemotherapy in preclinical models, a finding supported by the results of subsequent phase I/II trials in chemotherapy-naive non-small cell lung cancer (NSCLC) patients who received/carboplatin (P/C) combination therapy. The present study evaluated whether suramin enhances the activity of docetaxel in human NSCLC xenografts.Methods The in vitro effect of suramin on docetaxel activity was evaluated using 3-D histocultures of chemotherapy-naive A549 tumors. For in vivo activity evaluation, we first established the P/C pretreatment schedule that produced tumor growth inhibition, but not tumor eradication, and established the maximally tolerated docetaxel/suramin regimens. In the second study, P/C-treated animals received physiological saline, single-agent suramin (10 mg/kg), docetaxel (10 mg/kg), or the combination twice weekly for 3 weeks.Results The in vitro results showed that 20 μM suramin, which had no activity as single agent, enhanced the docetaxel activity (measured as 50% inhibition of DNA synthesis) by more than 10-fold. The in vivo studies showed reduced tumor growth by P/C (30% growth in 14 days vs. 75% in control). In contrast, docetaxel produced tumor regression (15% reduction) in P/C-treated animals, significantly reduced, on a cellular level, the viable cell density and the proliferating fraction (40% reduction for both measurements), and enhanced the apoptotic fraction 4-fold (p < 0.05 for all effects). Suramin had no activity or toxicity (measured as body weight loss) but significantly enhanced the docetaxel activity. Compared to docetaxel alone, the combination showed earlier onset of tumor size reduction, greater extent of tumor regression (31 vs. 15%), greater reduction of viable cell density and proliferating fraction (additional 15–25% reduction), and greater apoptotic fraction (additional 2.5-fold increase) (p < 0.05 for all parameters).Conclusions Results of the present study indicate that nontoxic suramin treatments enhanced the activity of docetaxel in P/C-pretreated A549 xenograft tumors in mice without enhancing host toxicity. These encouraging results provided the basis for phase I/II trials of docetaxel plus low-dose suramin in patients with NSCLC in second-/third-line settings.     

Radiosynthesis of [11C]docetaxel

Docetaxel (Taxotere®) is an accepted chemotherapeutic agent for the treatment of breast cancer and non‐small cell lung cancers. A potential means of predicting response is measuring tumor uptake of [¹¹C]docetaxel using Positron Emission Tomography (PET). The synthetic approach to introduce the ¹¹C isotope in the 2‐benzoyl moiety of docetaxel unfortunately was unsuccessful. The radiosynthesis of [¹¹C]docetaxel ( 6b , Scheme 1), with the ¹¹C isotope in the BOC moiety, was however, successful using a second synthetic approach. It started with the reaction of [¹¹C]tert‐butanol with 1,2,2,2‐tetrachloroethyl chloroformate to give [¹¹C]tert‐butyl‐l,2,2,2‐tetrachloroethyl carbonate in a good overall yield (62±9%). In the final step, the [¹¹C]tert‐butoxycarbonylation of the free amine of docetaxel gave [¹¹C]docetaxel 6b in a satisfactory decay corrected yield of 10±1% (from [¹¹C]CO₂). Copyright © 2004 John Wiley & Sons, Ltd.     

Quinoxaline and quinoxaline‐1,4‐di‐N‐oxides: An emerging class of antimycobacterials

Tuberculosis (TB) is a highly dreaded, infectious, chronic, airborne disease affecting more than two million people all around the world, with more than eight million cases every calendar year. TB is the second leading infectious cause of death after HIV/AIDS. Over the past few decades, numerous efforts have been undertaken to develop new anti‐TB agents. The current frontline therapy for TB consists of administering three or more different drugs (usually isoniazid, rifampin, pyrazinamide, and ethambutol) over an extended period of time. But these drugs will take 6–12 months to cure TB, along with many side effects; hence, there is an urgent need to explore new anti‐TB agents. Quinoxaline derivatives are a class of compounds that show a spectrum of biological properties and the interest in these compounds is exponentially growing within the field of medicinal chemistry. Quinoxaline‐1,4‐di‐N‐oxide derivatives have shown to improve the biological results and are endowed with anti‐viral, anti‐cancer, anti‐bacterial, and anti‐protozoal activities with application in many other therapeutic areas. Since quinoxaline derivatives are regarded as a new class of effective anti‐TB candidates, their 1,4‐di‐N‐oxide analogues may show promising in vitro and in vivo anti‐TB activities and might be able to prevent the drug resistance to a certain extent. Therefore, the main aim of this review is to focus on important quinoxaline and quinoxaline‐1,4‐di‐N‐oxide analogues that have shown anti‐TB activities, and their structure–activity relationships for designing anti‐TB agents with better efficacies. The present review will be helpful in providing insights for rational designs of more active and less toxic quinoxaline‐based anti‐TB prodrugs.

     

Alogliptin benzoate for the treatment of type 2 diabetes

Docetaxel (Taxotere?, Aventis Pharma), a semisynthetic taxane targeting the β-subunit of tubulin, has broad spectrum anticancer activity including non-small cell lung cancer (NSCLC). It is synergistic with platinum and radiation in preclinical models and has been tested clinically in every stage of NSCLC. Docetaxel–platinum combinations have an efficacy comparable to other newer-agent platinum doublets as first-line therapy in advanced NSCLC, and has been approved for use in this setting. Docetaxel was initially approved for NSCLC in the second-line setting following two Phase III trials demonstrating improved survival and quality of life. Ongoing clinical trials are investigating how best to combine docetaxel with thoracic radiotherapy in locally advanced disease. Preliminary studies evaluating docetaxel in the pre-operative setting have also been completed. Ongoing studies are focused on confirming the results observed with consolidation docetaxel in locally advanced NSCLC (SWOG 9504) and docetaxel in combination with molecularly targeted agents. This paper will review the pharmacology, preclinical, clinical and pharmacoeconomic data supporting the use of docetaxel in the treatment NSCLC.