Synthesis, electrophilic substitution and structure-activity relationship studies of polycyclic aromatic compounds towards the development of anticancer agents

Polycyclic aromatic hydrocarbons (PAH) are considered potentially carcinogenic. Substituted PAH derivatives, in contrast, may serve as anticancer agents, and as chemotherapeutics. This article presents a review of their use. Particular emphasis is placed on the synthesis of these new compounds, electrophilic substitution reactions and novel synthetic methodologies developed in our laboratory. Based on numerous reports and the data available, we believe that DNA-intercalating and membrane-interacting sites are the target for their effects.     

Development of new peptide vectors for the transport of therapeutic across the blood-brain barrier

The blood-brain barrier (BBB) is formed by the special nature of the endothelial cells of the brain capillaries characterized by tight junctions between cells and a high expression of efflux pumps only allowing the brain access to nutrients necessary for cell survival and function. These properties of the BBB result in the incapacity of small and large therapeutic compounds to reach the brain at therapeutic concentrations. Various strategies are now being developed to enhance the amount and concentration of these compounds in the brain parenchyma. The development of new technologies such as peptide vectors has the potential to achieve the delivery of active agents in therapeutic concentrations across the BBB to treat brain diseases such as brain primary and metastatic cancers and neurodegenerative disorders. In this review, the design of new active peptides and development of new peptide vectors for drug brain delivery using physiological approaches will be addressed. A new chemical entity incorporating angiopep peptide in a small anticancer agent (paclitaxel) is now in clinical trials. It is the first of such designed agents to be validated for the treatment of human brain cancers and opens the door for such approaches.     

Protein transduction by poly-arginine

Protein transduction methods have been developed utilizing the delivery of peptides and proteins into eukaryotic cells by the protein transduction domain (PTD). Initially, the PTD domain was developed from the sequences from HIV-1 TAT, HSV VP-22 and antennapedia homeoprotein. Recently, several novel PTDs were developed and has been used as a valuable strategy for transduction of therapeutic protein. We developed a novel, high efficiency PTD (11 arginine) based on the TAT sequence and used 11R for the regulation of intracellular signal cascades. PTD can deliver proteins and other bioactive compounds and therefore serves as a very useful strategy for the development of therapeutic agents.     

Therapeutic applications of lipid-coated microbubbles

Lipid-coated microbubbles represent a new class of agents with both diagnostic and therapeutic applications. Microbubbles have low density. Stabilization of microbubbles by lipid coatings creates low-density particles with unusual properties for diagnostic imaging and drug delivery. Perfluorocarbon (PFC) gases entrapped within lipid coatings make microbubbles that are sufficiently stable for circulation in the vasculature as blood pool agents. Microbubbles can be cavitated with ultrasound energy for site-specific local delivery of bioactive materials and for treatment of vascular thrombosis. The blood-brain barrier (BBB) can be reversibly opened without damaging the neurons using ultrasound applied across the intact skull to cavitate microbubbles within the cerebral microvasculature for delivery of both low and high molecular weight therapeutic compounds to the brain. The first lipid-coated PFC microbubble product is currently marketed for diagnostic ultrasound imaging. Clinical trials are currently in process for treatment of vascular thrombosis with ultrasound and lipid-coated PFC microbubbles (SonoLysis Therapy). Targeted microbubbles and acoustically active PFC nanoemulsions with specific ligands can be developed for detecting disease at the molecular level and targeted drug and gene delivery. Bioactive compounds can be incorporated into these carriers for site-specific delivery. Our aim is to cover the therapeutic applications of lipid-coated microbubbles and PFC emulsions in this review.     

1, 2, 4-Triazine N-oxide derivatives: studies as potential hypoxic cytotoxins. Part II

New 1, 2, 4-Triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The starting heterocycles have been prepared using a standard microwave oven in a clean and good-yielded process. The reactivity of methyl-1, 2, 4-triazine N(4)-oxide and N(1), N(4)-dioxide with different electrophilic agents has been studied. The desired products were obtained only when iminium electrophiles were employed. The regioselectivity of this process has been studied by means of experimental and theoretical (at ab initio level) procedures. Theoretically was expected that the most stable intermediates where the benzylic-like anion from position 5. A fact which agreed with the experimental observed regioselectivity. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than tirapazamine, 3-amino-benzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 19, 6-methyl-5-[2-(5-nitrothienyl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective.     

Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage

Genetic and biochemical evidence continues to implicate the production and accumulation of the Abeta42 peptide as the causative factor in Alzheimer's disease (AD). Thus, a variety of strategies have been developed to decrease the production and/or aggregation of this peptide, which may be clinically useful for the treatment of this devastating disorder. Recently, the discovery that some non-steroidal anti-inflammatory drugs (NSAIDs) appear to selectively decrease the production of Abeta42 has opened a novel therapeutic avenue for AD treatment that may circumvent potential toxicity associated with long-term global inhibition of gamma-secretase activity. One drug from this class of compounds, R-flurbiprofen, has advanced to phase 3 clinical trials and may soon provide insight into the viability of this strategy for the prevention or treatment of AD. Delineating the target and mechanism of these compounds is essential for developing new agents with increased potency and optimized pharmacologic properties. The evidence indicating that these chemicals modulate the production of Abeta peptides by directly interacting with the gamma-secretase complex is summarized.     

Drug combinations enhancing the antineoplastic effects of erlotinib in high-grade glioma

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Especially in this disease, qualitative and quantitative aspects render the dysregulated epidermal growth factor receptor (HER1/EGFR) an outstanding therapeutic target. A variety of therapeutic compounds was developed to target HER1/EGFR among which the clinically most advanced agents are small molecule tyrosine kinase (TK) inhibitors. Unfortunately, clinical studies examining their therapeutic efficacy have so far failed to document a major therapeutic break-through in the setting of GBM. Thus, the targeted approach against HER1/EGFR likely requires a synergistic drug combination strategy to ultimately become successful in this disease. This patents review focuses on innovative therapeutic strategies combining HER1/EGFR-targeted TK inhibitors with novel agents which for the most part have not been evaluated for the treatment of GBM yet but which constitute interesting candidates for further evaluation in this setting.     

用分子轨道法对倍半萜类抗癌剂构效关系的研究

本文列举35种倍半萜类抗癌剂的结构和活性,从中归纳出有强抗癌活性的必要条件是分子中必须具有含共轭π键的活性基团。采用CNDO分子轨道法模拟地计算了这些活性基团的E_LUMO,发现其E_LUMO愈低,其母体的抗癌活性就愈高,并且这些E_LUMO与RNA、DNA分子中碱基的E_LUMO的差值较小。作者据此提出了倍半萜类抗癌剂的两个亲电活性基团分别与RNA或DNA的双股核苷酸链上的碱基发生电荷转移络合的抗癌机理。     

Novel 1-haloalkyl-2-nitroimidazole bioreductive alkylating agents

Solid tumors contain hypoxic cells which are relatively resistant to radiation treatment and to most forms of chemotherapy. These cells can be preferentially targeted using chemotherapeutic agents that are specifically activated by cellular reductase enzymes in the absence of oxygen. A new class of bioreductive alkylating agents based on the 2-nitroimidazole nucleus has been developed which contains a haloalkyl substituent on the N-1 position of the imidazole ring. Compounds of this series were readily reduced by mammalian NADPH-cytochrome c reductase, and reduction led to the production of an electrophilic center. This reactive component was hypothesized to be responsible for the preferential cytotoxicity of the agents of this class to hypoxic tumor cells through alkylation of cellular components.     

Comparative pharmacology of the angiotensin II receptor antagonists

The non-peptide angiotensin II (AII) receptor antagonists are a new class of compounds that are continuing to be developed as therapeutic agents for the treatment of hypertension, heart failure (HF) and chronic renal disease (CRD). Several of these compounds are currently available for therapeutic use in the USA and the European community with several more in clinical trials and in development. Compounds in this new class are as effective as angiotensin converting enzyme (ACE) inhibitors in treating hypertensive patients and appeared to have a similar therapeutic profile to ACE inhibitors in patients with HF and CRD. One clinical advantage of the AII receptor antagonists over ACE inhibitors is an improved side-effect profile with the absence of the persistent dry cough associated with ACE inhibitor therapy. To date, it is clear that the AII receptor antagonists are effective antihypertensive agents. Clinical trials are currently in progress to determine the therapeutic efficacy of these drugs in the treatment of HF and progressive renal disease.     

Selective functionalization of small organic molecules using electrophilic nitrogen sources

Selective functionalization of small organic molecules using electrophilic nitrogen-containing reagents has been a long-standing challenge in organic synthesis. The delivery of nitrogen in the corresponding reactions can occur via a nitrenoid, radical or electrophilic pathway. Nitrogen transfer processes result in the rapid synthesis of diverse and useful products, such as aziridines, aminohalides, aminoalcohols, sulfimines and amines. This review outlines advances in the field during the past two years.     

Epidermal growth factor receptor tyrosine kinase inhibitors as anticancer agents

The epidermal growth factor receptor (EGFR)-driven autocrine growth pathway has been implicated in the development and progression of the majority of the most common human epithelial cancers, making the blockade of this growth pathway a promising anticancer therapeutic strategy. Different approaches have been developed to block EGFR activation and/or function in cancer cells. In the past 15 years, various anti-EGFR blocking monoclonal antibodies (MAb), recombinant proteins containing transforming growth factor-alpha (TGFalpha) or EGF fused to toxins, and tyrosine kinase inhibitors (TKIs) have been generated and their biological and potentially therapeutic properties characterised. One of these agents, MAb IMC-C225, a chimeric human-mouse IgG1 MAb, is the first anti-EGFR agent to enter phase II to III clinical trials in patients with cancer. Several small compounds that block the ligand-induced activation of the EGFR tyrosine kinase have been developed. Among these EGFR-TKIs, various quinazoline-derived agents have been synthesised and have shown promising activity as anticancer agents in preclinical models. ZD1839 ('Iressa'), an anilinoquinazoline, is an orally active, selective EGFR-TKI which is currently under clinical evaluation in phase II to III clinical trials in patients with cancer. Preclinical data for ZD1839 strongly support the possibility of potentiating the antitumour activity of conventional chemotherapy with agents that selectively block the EGFR.     

In Process Citation

The development of oncological therapeutic agents is a complex and risky process and it is mainly pursued by research-based pharmaceutical companies. Academic and public research institutions, however, have contributed to the finding and evaluation of basic scientific knowledge, which were transferred to the industry for co-development. Since 1960 increasing regulatory demands have caused a prolonged development time and dramatical multiplication of costs. Oncological research in Germany began shortly after the end of war, when Bayer worked on the ethyleneimino compounds with agents like E39 and trenimon for therapeutical use. Early in the fifties this focus of research changed to Asta-Werke, Bielefeld (later ASTA Medica, Frankfurt) where cyclophosphamide (Endoxan, Cytoxan), ifosfamide (Holoxan, Ifex) and trofosfamide were developed as worldwide leading alkylating cytotoxic agents. The detection of mesna (Uromitexan, Mesnex) used for the organospecific detoxification of urotoxic metabolites caused a further increase of the cancerotoxic selectivity and an improved safety of oxazaophosphorine therapy. There has been ongoing research on alkylating agents (mafosfamide, glufosfamide), and new therapeutic principles like miltefosine (Miltex) or hormonal agents like cetrorelix (LHRH-antagonist) are in development.     

Targeted drug delivery via folate receptors

Targeted delivery via selective cellular markers can potentially increase the efficacy and reduce the toxicity of therapeutic agents. The folate receptor (FR) has two glycosyl phosphatidylinositol (GPI)-anchored isoforms, α and β. FR-α expression is frequently amplified in epithelial cancers, whereas FR-β expression is found in myeloid leukemia and activated macrophages associated with chronic inflammatory diseases. Conjugates of folic acid and anti-FR antibodies can be taken up by cancer cells via receptor-mediated endocytosis, thus providing a mechanism for targeted delivery to FR+ cells. The aim of this article is to provide a brief overview of applications of FR targeting in drug delivery, with an emphasis on the strategy of using folate as a targeting ligand. In order to do this, recent literature is surveyed on targeted delivery via both FR sub-types, as well as new findings on selective receptor upregulation in the targeted cells. A wide variety of molecules and drug carriers, including imaging agents, chemotherapeutic agents, oligonucleotides, proteins, haptens, liposomes, nanoparticles and gene transfer vectors have been conjugated to folate and evaluated for FR-targeted delivery. Substantial targeting efficacy has been found both in vitro and in vivo. In addition, mechanisms and methods for selective FR upregulation have been uncovered, which might enhance the effectiveness of the FR-targeted delivery strategy. FR-α serves as a useful marker for cancer, whereas FR-β serves as a marker for myeloid leukemia and chronic inflammatory diseases. FR-targeted agents have shown promising efficacy in preclinical models and significant potential for future clinical application in a wide range of diseases.     

Solid-phase and combinatorial synthesis in beta-lactam chemistry.

Combinatorial chemistry has became a core technology for the rapid development of novel lead compounds in the pharmaceutical industry and for the optimization of therapeutic efficacy. The effort to prepare libraries of compounds by combinatorial chemistry has led to an unprecedented growth in solid phase organic synthesis (SPOS), particularly for the preparation of non-oligomeric small molecules. In this context, the clinically valuable b-lactam compounds are very attractive targets for research using these new techniques. In recent years, b-lactam compounds have been recognized not only as unique antibacterial agents but also as potent enzyme inhibitors, drug delivery agents, and versatile synthetic intermediates. This review gives a comprehensive up-date for the application of solid-phase and combinatorial synthesis to b-lactam compounds.     

Targeted drug delivery via folate receptors

Targeted delivery via selective cellular markers can potentially increase the efficacy and reduce the toxicity of therapeutic agents. The folate receptor (FR) has two glycosyl phosphatidylinositol (GPI)-anchored isoforms, alpha and beta. FR-alpha expression is frequently amplified in epithelial cancers, whereas FR-beta expression is found in myeloid leukemia and activated macrophages associated with chronic inflammatory diseases. Conjugates of folic acid and anti-FR antibodies can be taken up by cancer cells via receptor-mediated endocytosis, thus providing a mechanism for targeted delivery to FR+ cells. The aim of this article is to provide a brief overview of applications of FR targeting in drug delivery, with an emphasis on the strategy of using folate as a targeting ligand. In order to do this, recent literature is surveyed on targeted delivery via both FR sub-types, as well as new findings on selective receptor upregulation in the targeted cells. A wide variety of molecules and drug carriers, including imaging agents, chemotherapeutic agents, oligonucleotides, proteins, haptens, liposomes, nanoparticles and gene transfer vectors have been conjugated to folate and evaluated for FR-targeted delivery. Substantial targeting efficacy has been found both in vitro and in vivo. In addition, mechanisms and methods for selective FR upregulation have been uncovered, which might enhance the effectiveness of the FR-targeted delivery strategy. FR-alpha serves as a useful marker for cancer, whereas FR-beta serves as a marker for myeloid leukemia and chronic inflammatory diseases. FR-targeted agents have shown promising efficacy in preclinical models and significant potential for future clinical application in a wide range of diseases.     

Acid-base catalysis of chiral Pd complexes: development of novel asymmetric reactions

Using a unique character of the chiral palladium complexes 1 and 2, several types of novel catalytic asymmetric reactions have been developed. In contrast to the conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine compounds were activated to form chiral palladium enolates, which underwent the enantioselective Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid activating the electrophiles, formed concomitantly during the formation of the enolates, whereby the C-C bond-forming reaction was promoted. In addition, this palladium enolate chemistry was also applicable to the electrophilic asymmetric fluorination reactions, and thus various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, and oxindoles were fluorinated in a highly enantioselective manner (up to 98% ee). It is advantageous that these reactions were carried out in environmentally friendly alcoholic solvents such as ethanol, and exclusion of air and moisture is not necessary.     

Current state on development of neuroprotective agents for cerebral ischemia

The improvement of decreased cerebral blood flow using thrombolytic agents, anti-thrombin drugs, and antiplatelet drugs has been essential for acute ischemic stroke. Edaravone, a free radical scavenger, has been commercially available as a novel neuroprotective agent for ischemic stroke in Japan from 2001. The appearance of a neuroprotective agent implies that therapeutic strategy can be expanded through a combination with thrombolysis. In the previous development, several cases have reported that neuroprotective compounds failed in clinical trials. However, recent studies have clarified that the cerebral ischemia induced the neuronal cell death by mediating multiple mechanisms with necrosis and/or apoptosis. The cytotoxicity derived from the NO/peroxynitrite/free radical generating system, one of intracellular Ca2+ signaling, is a typical event in ischemic injury, which is protected by edaravone. Furthermore, it is suggested that suppression of excessively activated voltage-dependent Na+ and Ca2+ channels is effective as a strategy for neuroprotection, since abnormal excitatory stimuli in the neuronal network result in the cerebral infarction. The development of several compounds having different mechanisms of action for acute stroke is in progress. It is therefore prospected that the various novel neuroprotective agents will be provided for assuring the option of therapeutic strategy, since the reinforcement of medical stroke care including diagnosis contributes to the prolongation of the therapeutic time window.