Letters in Drug Design & Discovery - Volume 9, Issue 3, 2012

Cancer remains one of the leading causes of death in the world and as a result there is a pressing need for the development of novel and effective treatments. Cancer cells differ from their normal counterparts in a number of biochemical processes, particularly during the control of cell growth and division. Despite major breakthroughs in many areas of modern medicine over the past 100 years, the successful treatment of cancer remains a significant challenge at the start of the 21st century. Mainly because it is difficult to discover novel agents that selectively kill tumor cells or inhibit their proliferation without the general toxicity, therefore the use of traditional cancer chemotherapy is still very intense. In recent years, combination chemotherapy with different mechanisms of action is one of the methods that is being adopted to treat cancer. Therefore, a single molecule containing more than one pharmacophore, each with different mode of action could be beneficial for the treatment of cancer. Apoptosis or programmed cell death is an orderly cascade that can be regulated and ultimately results in the death of a cell in a neat and orderly manner. Recently anticancer efficacy of various chemotherapeutic agents has been correlated with their apoptosis inducing ability. Therefore identification of new molecules that induce apoptosis has become attractive for the discovery and development of novel anticancer agents. Microtubules are important in mitosis and cell division; they have been a target for the development of a number of new anticancer drugs. There are two major groups of these antitumor agents, microtubule stabilizers such as paclitaxel and microtubule destabilizers such as colchicine, combretastatin A-4, and vinca alkaloids. Natural products and synthetic organic cations that bind specifically and selectively to the DNA minor groove have therapeutic potential in a wide range of applications. These compounds bind to minor groove by a combination of ionic, hydrophobic and hydrogen bonding interaction. A significant number of papers, institutions and countries contribute to this special issue: the articles are mainly original articles, but some of them are devoted to new results and the related methods obtained/developed by the respective authors, who belong to prestigious research institutions in their field of medicinal chemistry. In total, 51 authors from 7 research institutions/universities located in 6 countries contributed to this special issue. I hope this special volume of LDDD will provide the reader with an understanding of anticancer research and its progress from the results that have been discussed.

Castrate-resistant prostate cancer is associated with resistance to apoptotic-triggered cell death mediated by elevated expression of anti-apoptotic proteins. In the current study, the ability of three titanocene derivatives to induce apoptosis in PC-3 cells is investigated and compared to docetaxel as the standard therapy as a first step in the pre-clinical testing of these compounds against advanced prostate cancer. Apoptosis triggered by the titanocene derivatives and docetaxel was assessed using propidium iodide DNA staining by flow cytometry. Bcl-2, the IAPs and Id-1 were manipulated in PC-3 cells by siRNA strategies and their corresponding protein expression determined by western blotting. The ring-substituted titanocene derivatives induced apoptosis in a time and dose dependent manner in PC-3 cells similar to that seen with docetaxel. Triple IAP knockdown (cIAP-1, cIAP-2 and xIAP), Bcl-2 and Id-1 resulted in an increased sensitivity to apoptosis induced by the titanocene derivatives but no strategy sensitized to docetaxel-induced apoptosis. Down-regulation of Bcl-2, the IAPs and Id-1 may be potential target to increase sensitivity of castrate-resistant prostate cancer to the titanocene derivatives. It is vital not only to understand tumor biology, but also understand how individual drugs exert their effects. Combining this knowledge will ensure that we can effectively tailor therapeutic strategies for the treatment of androgen-independent prostate cancer.

A series of pyridylimidazolidinone linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates have been synthesized and evaluated for their DNA binding ability and cytotoxicity. These conjugates exhibited significant DNA binding ability and potent anticancer activity with GI50 values in the range of 0.2-3 μ M.

A new series of bisindole based sulfonates (4a-t) have been synthesized and evaluated for their anticancer activity against various human cancer cell lines. Some of these compounds exhibited good inhibitory activity against most of the cell lines tested. Interestingly all the compounds from the bisindole sulfonate series exhibited selective inhibition against MCF-7 cell line. Further these compounds have also been tested for their inhibition of tubulin polymerization. The compounds 4a, 4l, 4n, 4r and 4t demonstrated a dose dependent tubulin inhibition with IC50 values of 2.3, 1.7, 8.1, 6.0 and 10 μM, respectively. Thus, results have demonstrated that antiproliferative activity of these compounds is related to their inhibition of tubulin polymerization.

A series of fourteen polysubstituted 7-chloro-4-quinolinylhydrazone derivatives (3a-n) has been synthesized and evaluated for their activity against four cancer cell lines. Among them, compounds 3a, 3c, 3h, 3i, 3j and 3n showed good cytotoxicity (with IC50 ranging from 0.7483 to 5.572 μg/mL). In general, we observed that the presence of methoxy groups on benzene ring plays an important role in the anticancer activity of this series, especially when they are located in 3,4 (3h) or 3,4,5 (3j) positions. These derivatives could be considered a relevant finding towards the rational design of new leads for antitumoral agents.

A series of 14 N-acyl-hydrazones L-serine derivatives have been synthesized and evaluated for their in vitro antitumoral activities against four neoplastic cancer cells: HL-60 (leukemia), MDA-MB-435 (melanoma), HCT-8 (colon) and SF-295 (nervous system). Five compounds (3g, 3h, 3i, 3k and 3n) were considered active against at least two cancer cell lines, with more than 90% of growth inhibition. Compound 3h, with IC50 of 2.04 μg/mL, seems to be moderately selective to HCT-8 and can be considered in further studies aiming new prototypes for a lead molecule against colon cancer.

New advances in chemistry and biology have lead to the development of innovative approaches towards the treatment of deadly diseases like cancer. Particularly, glycochemistry and glycobiology have passed through a renaissance in the last two decades. This is apparent from the fact that the recent advances in the synthesis of tumor associated carbohydrate antigens (TACAs) have led to the development of various anticancer vaccines undergoing clinical trials. Fully synthetic anti-cancer vaccines targeting tumor-associated carbohydrates provide an attractive option for the treatment of cancer. Such vaccine candidates have major advantages as they can be designed to incorporate only those elements required for a desired immune response, and can be produced in a reproducible manner. Recent developments in the synthesis of complex carbohydrates and glycopeptides have made it possible to construct such glycoconjugate vaccine candidates.

A series of 3-[3-[4-(Substituted)-1-cyclicamine]propyl]thio-5-substituted[1,2,4]triazoles (8a-j) were synthesized with good yields starting from corresponding carboxylic acids. The cytotoxicity studies of these derivatives were studied against five different human cancer cell lines. Three compounds had shown good anticancer activity. The triazole derivatives, 8i and 8j were most potent particularly against U937 and HL-60 cells. The cytotoxic potency of the compounds varied between the cell lines suggesting that a structural property of these compounds as possible determinants of their biological activity.

5-Substituted uracils were reported to be important core structure of diverse therapeutics. Herein, novel mixed ligand transition metal (Mn, Cu, Ni) complexes of 5-iodouracil (5Iu) with 8-hydroxyquinoline or 8HQ (1-3) and 5- nitrouracil (5Nu) with 8HQ (4-6) have been synthesized. The metal complexes 1-6 exert significant cytotoxicity against HepG2, A-549, HuCCA-1 and MOLT-3 cell lines. Particularly, the cytotoxicities of tested complexes against HepG2 cells show their IC50 values lower than the reference drug. Cu complex of 5Nu (5Nu-Cu-8HQ, 5) is the most potent and promising cytotoxic compound. Mn complex of 5Iu (5Iu-Mn-8HQ, 1) is shown to be the most potent antioxidant. This finding reveals the application of using simple and commercially available bioactive ligands like 5Iu, 5Nu and 8HQ for the design and construction of new lead compounds with significant and promising bioactivities.

Quantitative relationships between structure of the selected 4-chloro-2-mercapto-5-methylbenzensulfonamide derivatives and their potential anticancer activity were studied. Molecular descriptors of studied compounds were obtained with the support of Dragon software after geometry optimization using HyperChem package. Theoretically calculated parameters were used to study the relationships between structure and activity. Principal component analysis performed firstly on activity data and secondly on different kinds of molecular parameters' sets revealed similar results, which allowed to divide studied set of compounds into three distinct clusters diversifying them in both structure and activity.

The estrogen receptors (ERα and ERβ ), are ligand inducible nuclear receptors which play a key role in many cellular functions through specific gene expression regulation. The estrogen receptor is regarded as an attractive therapeutic target for hormone-dependent breast cancers. The antiestrogen drug tamoxifen is useful in the treatment of breast cancer. To develop new ER targeting agents as probes of estrogen receptor action, the synthesis and preliminary biochemical evaluation of five structurally varied estrogen receptor ligand conjugates containing the tamoxifen metabolite endoxifen are now reported. These structurally varied conjugates bind to the estrogen receptor (commonly overexpressed in breast cancer cells) and contain DNA alkylating, aromatase inhibitor and COX2 inhibitor moieties. The ER targeting group endoxifen (E/Z 4-hydroxy-N-desmethyltamoxifen) was selected for its ability to bind to the estrogen receptor. Compound 11 exhibited moderate antiproliferative activity IC50 = 1.64 μM in MCF-7 breast cancer cells, while compound 9b demonstrated the most potent ER binding effects with IC50 values of 35.6 nM(ERα), 19.5 nM(ERβ ).

The synthesis and structure-activity relationships (SAR) antitumor activities of monopyrazolic and bipyrazolic tripodal derivatives are reported here for the first time. The ten products were tested against three human cancer cell lines including breast (MDA-MB231), prostate (PC3) and colorectal (LoVo) cancers. In bipyrazolic series, most of them exhibited a moderate antitumor activity against three human cancer cell lines with an order of 5 > 7 > 8 in case of colorectal cancer and 5 > 7 ≈ 8 in case of breast and prostate cancers.

In the present study, some hydrazone derivatives were synthesized via the reaction of 3-cyclohexylpropionic acid hydrazide with various benzaldehydes. The chemical structures of the compounds were elucidated by spectroscopic techniques such as IR, 1H-NMR and FAB-MS and elemental analyses. The compounds were evaluated for their antiinflammatory and cytotoxic activities. Anti-inflammatory activity was determined in terms of inhibition of NF-κB, ROS generation and iNOS activity. Several derivatives inhibited NF-κB and iNOS, but no effect was observed on intracellular ROS generation. Furthermore no cytoxicity was observed. Biological activity compared with the chemical structural information suggests that different functional groups on the phenyl ring influence the physicochemical properties and thus modulate biological activity.

With an objective to evaluate the antibacterial activity of triazine derivatives, a series of 2,4,6-trisubstituted- 1,3,5-triazine were synthesized and characterized by FTIR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. The minimum inhibitory concentration (MIC) of the compounds that displayed favourable zone of inhibition was determined by broth microdilution method. Derivatives with morpholinyl substituent (4a and 4i) demonstrated good in vitro activities against Gram-positive organisms, whereas two of the compound bearing a diethylamino side chain exhibited moderate (4e) to broad spectrum (4j) activity comparable to streptomycin. The promising activity of the latter maybe attributed to the substitution of electron releasing group at para position of phenyl rings.

A novel series of asymmetric 4-aryl-1,4-dihydropyridine (1,4-DHP) 3,5-diester derivatives and their symmetric analogues comprised of functional moieties of amlodipine, riodipine and cerebrocrast have been synthesized. The calcium channel blocking activity was evaluated in an isolated rat aortic ring model. The calcium overload preventing activity was tested in SH-SY5Y neuroblastoma cell line by a fluorescence-based calcium assay. Among synthesized and tested compounds, 4a showed the highest calcium overload preventing activity (IC50=39μM) and 7e demonstrated the highest calcium channel inhibiting activity (EC50=0.2 nM). Asymmetric ester 7a exerted both substantial calcium channel blocking and calcium overload preventing activity.

Due to overwhelming generation of drug resistant microorganisms, there is an urgent need to develop novel chemotherapeutic agents. In continuation of our research on discovery of novel heterocyclic scaffolds from 1,3,5-triazine, present study deals with design and development of some novel di- and tri-substituted 1,3,5-triazine derivatives. The synthesis of title analogues were accomplished by SNAr reaction and subsequently underwent rigorous antibacterial screening against a panel of representative Gram-negative and Gram-positive bacteria. Screening results revealed that minor structural variation may induce drastic changes in activity. Whereas, amine bridge and piprazine was termed as pivotal structural fragments necessary for generation and escalation of bio-activity. The structures of newly synthesized compounds were ascertained on the basis of their analytical and spectral profiles.

Flutamide (FLT) is the only presently recommended drug for monotherapy of benign prostatic hypertrophy. It is known for its poor solubility and slow dissolution. In this study nine different formulae of liquisolid systems (LS) were prepared using Polyethyleneglycol 400 as a liquid vehicle, Avicel® PH 102 and Aerosil 200 as the carrier and the coating material, respectively. Hydrophilic polymers (PVP, HPMC and PEG 2000) were added at a 10% w/w concentration to improve LS properties. Thermal analysis showed complete absence of drug crystallinity in the prepared LS that indicates successful FLT solubilization. The prepared systems were tested for their micromeritic properties (angle of repose, Carr's index and Hausner's ratio). The results showed that all the formulae had acceptable values of the angle of repose except formulae F2 (42.0) and F3 (43.50) indicating reasonable flow properties of the LS systems. Compressed into tablets, formula F8 showed the fastest drug release with about 69% of the drug released after the first 5 minutes and almost all the drug released after one hour. Directly compressed FLT tablets showed very slow release with only 5% and 30% of the drug released after 5 and 120 minutes, respectively.