References

A. Bowden, T. Biichner, B. E. de Pauw, S. G. Filler, M. A. Ghannoum, M. Glauser, R. Herbrecht, C. A. Kauffman, S. Kohno, P. Martino, F. Meunier, T. Mori, M. A Pfaller, J. H. Rex, T. R. Rogers, R. H. Rubin, J. Solomkin, C. Viscoli, T. J. Walsh, and M. White, Clin. Infect. Dis., 25, 43-59 (1997). 2. W. G. Powderly, AIDS Res. Hum. Retroviruses, 10, 925-929 (1994). 3. D. W. Denning and D. A. Stevens, Clin. Inf. Dis., 12, 1147-1201 (1990). 4. J. H. Rex, M. G....

Dendritic Cell Immunotherapy

The successful induction of cell-mediated antitumor immunity relies on the efficient capture of antigen by antigen-presenting cells, antigen processing, and presentation to T-lymphocytes. Antigen presenting cells (APC) such as B-cells, macrophages, and dendritic cells display antigenic peptides in the context of major histocompatibility complexes (MHC) to T-cells. Although B-cells and macrophages are capable of antigen uptake, processing, and antigen presentation, these APC are ineffective...

X5

In vitro, and they seem to act at the point of heme sequestration (1044). The antimalarial effect occurred during the second half of erythrocytic cycle, when free heme production peaks (1045). dl-a-Difluoromethylornithine and dl-a-monomethyldehydroornithine methyl ester, inhibitors of ornithine decarboxylase, part of the polyamine biosynthesis pathway, block exoerythrocytic schizogony (1046). The immunosuppressive agent deoxyspergualin (96) has shown activity in vitro and in vivo, most likely...

Wiu48999

Possess IC50 values in the nanomolar range (1031), although the oral activity was poor. had IC50 values in the range of 30-80 nAf against P., falciparum in vitro. Generalizations about SAR in this series were presented. More complex tetraoxanes could be prepared from steroidal ketones one compound derived from a cholic acid amide (91) was almost as active as artemisinin and displayed low cytotoxicity (1038)A hydroperoxide, 15-hydroper-oxyeicosatetraeneoicacid (HPETE),induced a 96 inhibition of...

Inhibitors of HCV NS3 Protease

TheNS3-dependent cleavage sites of the polyprotein have a consensus feature with cleavage occurring after cysteine (at the three intermolecular cleavage sites) or threonine (at NS3-4A intramolecular cleavage site) (Table 10.3). Other conserved features are an acid residue in the P, position (aspartic acid or glutamic acid), a small residue (serine or alanine) in Pr, and a hydrophobic residue in the P4- position (332). Crystal structural studies have shown that...

Structure Activity Relationship From the many series of azoles that have been re

Ported by diverse groups, several common structural features emerge an imidazole or triazole heme-coordinating group, a halo-substituted aromatic separated from the azole moiety by two atoms, and a side chain (see Fig. 17.4). The latter represents the feature of greatest diversity across the family. Early postulates that the halo-substituted aromatic residue binds in the pocket normally occupied by the A B-ring region of lanosterol (see conformational depiction in Fig. 17.4) now seem less...

Nucleoside Derivatives

To promptly identify an anti-poxvirus drug that could be immediately available in the event of a bioter-rorism attack, initial attention has focused on currently approved antiviral agents. Recent preclinical studies against vaccinia and cow-pox viruses have identified cidofovir (CDV) as a promising candidate. Cidofovir was first described in the literature in 1987 by De Clercq and Holy (467) and was approved in 1996 by the U.S. FDA as an intravenous treatment for...

Introduction

Selective toxicity was popularized by Professor Adrian Albert beginning with his lectures at University College London in 1948 and the first edition of his book in 1951. Subsequent editions appeared until the seventh edition in 1985 (1)The latter was reprinted in Japanese as two volumes in 1993 and 1994 (2, 3). Today, the concept of selective toxicity largely is limited to chemotherapy and antibiotic therapy. How does one design a cancer chemotherapeutic agent that will kill a malignant cell...

Info

Fore may be more susceptible to mutations be- Rb was the first human tumor suppressor gene identified, and the loss of RB protein function leads to malignancy. The RB protein is localized in the nucleus where it is either phosphorylated or unphosphorylated (Fig. 1.10). When unphosphorylated, RB binds to the E2F transcription factor and prevents transcriptional activation of E2F target genes. This normally occurs during the M and early G1 phases of the cell cycle. During late Gl, S, and G2...

Parasite Biochemistry and Genetics

The biology, biochemistry, and genetics of Plasmodia are topics of wide interest. The information from those fields that more directly impacts on the design of new antimalarial agents is presented briefly. For the majority of their life cycle in humans, malaria parasites live in red blood cells. Within the erythrocytes, the parasites feed on hemoglobin, digesting the protein as a source of amino acids and releasing heme Fe(II)pro-toporphyrinEX . Disruption of hemoglobin ca-tabolism results in...

Current Trend in the Management of Organ Transplantation

In recent years, a greater understanding of the immunobiology of graft rejection, coupled with progressive improvements in the surgical and medical management, has revolutionized the field of clinical transplantation. Newer im-munosuppressive schedules continue to be designed, not only to reduce the risk of rejection, but also to obtain a better therapeutic index that allows a further improvement of the graft Figure 12.1. Principal pathways of T-cell activation that follow engagement of the...

Pharmacokinetics and Metabolism

3,1,2.3.1 Sulfonamides, The sulfonamide drugs vary widely in their pharmacokinetic properties (Table 13.2). Those that are highly ionized are not absorbed from the GI tract after oral administration, leading to a high local concentration of the drug, and were thus considered useful for enteric infections. A majority of the sulfonamides, however, are well absorbed, mainly from the small intestine, and insignificantly from the stomach. Absorption occurs of the un-ionized part, related to their...

Side Effects Toxicity and Contraindications of the Macrolide Antibiotics

The majority of side effects associated with macrolide antibiotics are mild and transient in nature. The most frequently reported events in adults are diarrhea, nausea, abnormal taste, dyspepsia, abdominal pain (substantially less with newer macrolides), and headache. Like other kinds of antibiotics, pseudomembranous colitis has been reported with macrolide use, ranging in severity from mild to life-threatening. There have been isolated reports of transient central nervous system side effects...

W

Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Abstr. 571 (1999). 376. R. C. Gadwood, L. M. Thomasco, and D. J. Anderson, U.S. Pat. 5,977,373 (1999). 377. S. Bartel, R. Endermann, W. Guamieri, et al., Proceedings of the 37th IUPAC Congress, Berlin, Germany, Abstr. SYN-2-140 (1999). 378. S. Raddetz, S. Bartel, W. Guamieri, et al., WO 9940094 (1998). 379. S. Bartel, W. Guamieri, D. Habich, et al., WO 9937652 (1999). 380. J.A.Tucker, D. A Allwine, K. C. Grega, et al., J. Med....

Oh

Image Parahydroxybenzanamide Com

(32) is the most prominent (302).Many partial and total syntheses of taxol have been reported but none of these has as yet proved to be practical. Despite a long tradition allowing the discoverer to name an important compound, taxol was renamed paclitaxel for commercial purposes by the CRADA winner, Bristol-Myers Squibb. 4.1.1. Clinical Uses. Taxol is widely used in combinations for the therapy of refractory ovarian, breast, lung, esophageal, bladder, and head and neck cancers. 4.1.1.2 Side...

Dendritic Cells Transduced with Viral Vectors

One promising strategy for the future of im-munotherapy is transduction of DC with recombinant, replication-incompetent viruses expressing multiple or single tumor antigens, cytokines, or co-stirnulatory molecules. The goal of DC-based immunotherapy using viral vectors is to express one or more transgenes in DC so that endogenous and exogenous presentation of antigenic tumor peptides occurs in a favorable immunostimulatory environment using the complete repertoire of co-stimulatory molecules...

Epoxides and Aldehydes

Epoxides and simple aldehydes are highly reactive functionalities that readily alkylate nu-cleophilic groups such as amino, hydroxyl, and thiol on proteins and nitrogens on nucleic acids. Because of their high toxicity to higher organisms, they are used mainly to disinfect inanimate objects. 2.8.1 Epoxides. Ethylene oxide (oxirane, 20) is a colorless flammable gas. It readily dif- fuses through porous materials and destroys all forms of microorganisms at room temperature (48). Ethylene oxide is...

Clinical Use of Macrolide Antibiotics and Currently Used Drugs

Macrolide antibiotics belong to the family of macrocyclic antibiotics and are a well-established class of antibacterial agents for both human and veterinary applications. They have been used for the treatment of various bacterial infections in both out-patient and in-patient settings for more than 40 years, and as a result of their very good safety profile, they are extensively prescribed to children. The term macrolide means large macrocyclic lactone and was first used by R. B. Woodward for...

U9

Contagious, Superficial Disease Epidermophyton, Microsporum, Trichophyton spp. Aspergillus spp. Blastomyces dermatitidis Candida spp. Cladosporium, Fonsecaea, and Phialophora spp. External ear, lungs, eye, brain Lungs, skin, bone, testes Respiratory, gastrointestinal and urogenital tracts skin Skin Lungs, skin, joints, meninges Lungs, meninges Lungs, spleen, liver, adrenals, lymph nodes Nasal mucosa, lungs, blood vessels, brain Skin, nasal mucosa, lungs, liver, adrenals, lymph nodes External...

Biological Activity and Side Effects

The clinical use of amsacrine is mainly in acute myeloid leukemia. Amsacrine etoposide therapy with or without azacitidine in relapsed childhood acute myeloid leukemia was effective (34 complete responses), with aza-cytidine not improving response rates (187). Recent successful use in various adult leuke-mias has also been reported (188-190) .Amsacrine has generally not been successful in the treatment of solid tumors, except for some responses in head-and-neck cancer, where highdose amsacrine...

Recent Developments in the Macrolide Antibiotic Field

4.6.1 Novel Macrolides to Overcome Bacterial Resistance. Several macrolide derivatives having potent antibacterial activity against erythromycin-sensitive strains and at the same time with moderate activity against erythromycin-resistant S. pyogenes were first reported in 1989 265 .The 11,12-carbamate clarithromycin analogs and the 11,12-carbon-ate erythromycin analogs with additional modifications at the 4' position of the cladi-nose were found to be active against both in-ducible and...

Dyes

Polyhexamethylene Biguanide Mouthrinse

Organic dyes were used extensively as antimicrobial agents before the development of sulfonamides and antibiotics. Now only a few dyes such as gentian violet and methylene blue are used. Gentian violet hexamethyl-p-rosaniline chloride, 31 is a triphenylmethane dye that is converted into a colorless form leu-cobase in alkaline solution Equation 13.7 . Cationic dyes such as gentian violet generally are active against Gram-positive bacteria and fungi however, acid-fast and Gram-negative bacteria...

Heavy Metals

In the past, mercuric chloride was used widely as an antisep tic, but its present use is limited to disinfecting instruments and occasional application to un-abraided skin. The most significant inorganic mercury compound is ammoniated mercury Hg NH2 Cl , which is used for skin infections such as impetigo. It is formulated as ammoniated mercury ointment, which contains 5 or 10 of the compound in liquid petrolatum and white ointment. Mercuric oxide HgO is used sometimes...

Inhibitors of NS5B RNADependent RNA Polymerase The HCV NS5B protein which encodes RNAdependent RNA polymer

Ase RdRp activity, involves in the synthesis of complementary - -RNA using the genome as the template and the subsequent synthesis of genomic RNA using this - -RNA. In addition to its important role in the viral RNA replication, the NS5B amino acid sequence is highly conserved among different HCV strains, this protein has been considered as an attractive target for antiviral therapy 377, 380 . Biochemical and kinetic characterizations and the crystal structure of this enzyme have been reported...

Cd95

Hsv Ganciclovir Apoptosis

Mechanisms of thymidine kinase TK ganciclovir GCV -induced apo-ptosis. TK phosphorylates the nontoxic prodrug GCV to GCV-triphosphate GCV-PPP . which causes chain termination and single-strand breaks on incorporation into DNA. TWGCV induces p53 accumulation, which can cause translocation of preformed death receptor CD95 from the Golgi apparatus to the cell surface without inducing de novo synthesis of CD95. The signaling complex then is formed by CD95, the adapter molecule...

History and Biosynthesis of the Aminoglycoside Antibiotics

Walksman and colleagues discovered the first aminoglycoside antibiotics, streptomycin in 1944 and neomycin in 1949, using systematic searches for antimicrobial compounds derived from soil organisms 74,75 . These antibiotics were rapidly incorporated into clinical use, streptomycin being the first antibiotic with potent antimvcobacterial activity used for the treatment of tuberculosis. The discovery of these antibiotics was followed by the identification of numerous additional members of the...

Ci

2.1.4 Newer Not Commercially Available Selective Approaches to Cancer Chemotherapy 2.1.4.1 Paclitaxel Antibody Conjugate Comparative Cytology . The rationale for this project was to combine the best properties of two drug types and overcome each of their undesirable characteristic-Paclitaxel is a very effective anticancer drug but has poor solubility and lacks tumor specificity. Monoclonal immunoglobulins have good solubility properties and better tumor specificity, but lack good therapeutic...

Use of Radioprotective Agents in Radiotherapy and Chemotherapy of Cancers

Use of radioprotective agents to augment the effects of either radiotherapy or chemotherapy of various types of cancer has been investigated for 30 years or more, but until recently little positive benefit was observed. It is now clear that selective concentrations of protective agents can be realized in normal tissues, and that tumors are protected to a lesser extent. Favorable timing schedules for administering protective agents and anticancer therapies have played a significant role in the...

Structure Of Erythromycin 9 11 Imino Ether

E, erythromycin C, clarithromycin A, A-62671 R, roxithromycin EA, eiythromycylamine D, dirithromycin F, flurithromycin AZ, azithromycin MRSA, methicillin-resistantStaphylococcus aureus. 6,9 9,12-spiroketal 34 involves the action of C-12 hydroxyl group on the C-8-C-9 olefin. Chemical modification aimed at these functional groups i.e., at positions C-9, C-8, C-6, and C-12 was attempted in search of stable derivatives with antibacterial activity. 4.4.1 C-9 Ketone...

Clinical Use of Aminoglycoside Antibiotics and Currently Used Drugs

Aminoglycoside Drugs Photo

The aminoglycoside antibiotics find use as broad-spectrum agents for the treatment of infections caused by aerobic Gram-negative and Gram-positive bacteria including Klebsiella pneumoniae, Pseudomonas aeruginosa, E. colif Proteus sp., Serratia marcescens, and Staphylococci 45 . Aminoglycosides are also used in combination therapy with penicillins for the treatment of enterococcal infections. Some compounds such as paromomycin have been employed in treatment of protozoal infections 46 ....

Antibody Toxin Conjugates

Maytansinoid Dm1

This is a direct development of the immunotoxin approach, again exploiting the fact that many types of tumor cells present characteristic tumor-associated antigens on their surface 391 . Despite much work, this approach has not been particularly successful until recently, with a combination of the availability of more resurgence of interest. The hypothesis is that conjugation of toxic drugs to the antibodies deactivate the drug by limiting diffusional access to cells without...

Monobactams and Nocardicins

The isolation of the nocardicins in 1976 428 and the monobactams in 1981 429, 430 revealed for the first time the potential for antimicrobial activity in simple monocyclic j3-lac-tam structures as opposed to the fused-ring systems of the penicillins and cephalosporins. This provided great impetus for new ideas on the structural features necessary for j3-lactam Table 14.11 Penems Selected for Detailed Investigation

Inhibitors of HCV NS3 Helicase

The helicase activity associated with HCV NS3 protein has also been targeted for potential therapeutic intervention 369 . The crystal structure of this enzyme has been determined to provide insights into the mechanism of unwinding 369-372 . In addition to unwinding dsRNA, this enzyme also unwinds dsDNA 373 . Using a DNA duplex substrate and recombinant HCV NS3 produced in E. coliy Biochem Pharma recently reported an assay system for HCV NS3 helicase activity that might be suitable for...

Mizoribine

Mizoribine is a naturally occurring molecule isolated from the filtrate of culture medium of Eupenicillium brefeldia-num M-2166 from the soil in 1974 by Mizuno et al. 305 . 2.3.4.2 Chemical Structure. Mizoribine is a novel imidazole nucleoside 12 Fig. with a strong immunosuppressive activity. 2.3.4.3 Pharmacokinetics. Mizoribine is mainly excreted by the kidney 306 therefore its plasma concentration depends greatly on renal function. Dosage adjustment is thus required when MIZ...

Ldcpa

Stereoisomers based on L-phenylalanine. Figure 7.13. Stereoisomers based on L-phenylalanine. Other than its use as an analytical tool, the optical rotation does not provide information as to the molecule's shape, which, of course, determines fit at the receptor. Figure 7.13 contains drawings for a group of drugs based on L-phenyl- alanine or L-tyrosine. R- and -Amphetamine and R- and S-methamphetamine are centrally acting stimulants that exhibit complex pharmacology and high abuse...

Radiosensitizers 21 Introduction

Radiosensitizers were developed for use in cancer therapy 37-39, 343 . It is important for this purpose that they have a differential i effect on the tumor vs. the normal tissue. Otherwise, nothing would be gained over increas-i- ing the dose of radiation. The relative increase antitumor efficacy compared to normal tissue toxicity is referred to as therapeutic gain. of the compounds or strategies listed in chapter have yet to be proven useful in cancer therapy, but are of mechanistic interest....

Mccaleb R. Cancer Research

Pharm. Res., 21, 385 1998 . N. Amishiro, S. Nagamura, E. Kobayashi, K. Gomi, and H. Sato, J. Med. Chem., 42, 669 N. Amishiro, A. Okamoto, C. Murakata, T. Tamaoki, M. Okabe, and H. Saito, J. Med. Chem., 42,2946 1999 . M. Hidalgo, E. Izbicka, C. Cerna, L. Gomez, E. K. Rowinsky, S. D. Weitman, and D. D. von Hoff, Anti-Cancer Drugs, 10,295 1999 . M. Cristofanilli, W. J. Bryan, L. L. Miller, A. Y. C. Chang, W. J. Gradishar, D. W. Kufe, and G. N. Hortobagyi,...

Dendritic Cell lmmunotherapy Approaches for Undefined Tumor Antigens

An important issue in optimizing DC vaccines is choosing an ideal tumor antigen for DC loading Tumor cell lysates, apoptotic tumor bodies, and tumor cells can be used as immunogens in E C cancer therapy for the development of anti-tumor strategies. For several tumor types, antigenic epitopes are unknown. In contrast to peptide immunotherapy, using tumor-derived products bypasses the need to consider HLA haplotypes and the identification of specific tumor-derived antigens. Several of these...

Nucleoside Analogs it94Hy

Droxy-2- hydroxymethyl butyl guanine H2G, omaciclovir ll is an acyclic guanosine analog similar in structure to ACV. H2G is roughly comparable in activity to ACV against HSV-1, 20- to 400-fold more active against VZV, and somewhat less active against HSV-2 320, 321 , with a toxicity profile similar to ACV. H2G is efficiently phosphorylated by viral thymidine kinases 322 , and the triphosphate form is maintained at levels more than 170fold higher than for ACV in VZV-infected cells 321 . The...

Methisazone Marboran Ofthenon

Nucleoside compounds, methisazone 194 , a thiosemicarbazone derivative of isatine 110 , is worthy of note. In the early 1960s, Bauer et al. first showed that methisazone protected infant mice from fatal encephalitis caused by intracerebral injection of variola virus 464 . Around that time methisazone was used in a case of eczema vaccinatum and this appeared to be the first clinical use of antiviral drug in man 464 . As discussed above, clinical experience with methisazone has also included the...

Trastuzumab Herceptin Trastuzu

Herceptin Chemical Structure

Is a prototype for future antibody-based immunotherapeutics. It is a recombinant DNA-produced, humanized monoclonal antibody IgGj-x chain containing human framework regions and complementarity determining regions CDRs of mouse monoclonal antibody, 4D5 34 . It selectively binds to the extracellular domain of the human epidermal growth factor receptor-2 EGF-2 , also known as Her-2 with an affinity of 5 nM. The Her-2 protein is overexpressed on approximately 2530 of primary human breast tumors as...

Inhibitors of Picornaviral Attachment and Uncoating

Troponin Inhibitor Compound

Many picornaviruses share a common icosahedral cap-sid architecture constructed from 60 copies cf four proteins VPl, VP2, VP3, and VP4 revealed by crystallographic studies of several human enteroviruses namely, coxsackievirus B3, echovirus 1, poliovirus types 1, 2, and 3 and rhinovirus types 1A, 2 207 , 3,14, and 16 see references cited in Ref. 208 . VPl, VP2, and VP3 compose the viral surface, whereas VP4 lays interior at the capsid RNA interface 209 . In all of...

The Total Synthesis of Cephalosporin

Intermediates such as 79 329,330 have been used to provide the cephalosporin lactone ring system 80 and deacetylcephalothin 331 .Later, by use of a 2 2 cycloaddition reaction between the thiazine 81 and the ketene derived from azidoacetyl chloride, the total racemic synthesis of cephalothin was achieved 332-334 . To date, however, the only complete synthesis of cephalosporin C is that described by Woodward in his Nobel lecture of 1965 and published in 1966 335, 336 Figs. 14.9 and 14.10 ....

Phenols

Phenol was introduced by Lister as a surgical anesthetic in 1867. Originally, it was used undiluted and was toxic to tissue however, it was considered to be less harmful than potential infections. Lister subsequently found that dilutions as low as 1 40 still gave effective antisepsis. The development of substituted phenols and bisphenols with superior antiseptic activity and lower toxicity has led to phenol being replaced as an antiseptic. It has limited use as a preservative...

Inhibitors of RSV and Paramyxoviruses Fusion Proteins

Fattiviracin Biosynthesis

In a series of reports, investigators at Wyeth-Ayerst Research described the discovery of a family of novel anti-RSV agents including CL-309623 64 , CL-387626 65 , and RFI-641 66 163- 166 . The discovery began by screening of a compound library against a panel of viruses, and it turned out that CL-309623 was the only one to be remarkably effective and specific in inhibiting RSV infection. Interestingly, this compound was synthesized some 40 years ago as a brightener...

Mycophenolate Mofetil

Mycophenolate mofetil MMF RS 61443 is a semisynthetic derivative of the antimetabolite mycophenolic acid. Mycophenolicacid MPA was initially derived from the cultures of the Penicillium species by Gosio in 1896 282 and purified in 1913. Its antibacterial and antifungal activities were recognized in the 1940s. It was not until the 1980s that Nelson, Eugui, and Allison of Syn-tex, USA considered MPA for use as an immunosuppressant, as part of their search for selective...

Antifolates

Antifolate Fpgs

Antifolates interfere at various points in the process folic acid metabolism that provides the one-carbon unit required to convert deoxyuridine monophosphate to thymidylic acid for synthesis of the pyrimidines Fig. 2.7 . They are also key intermediates in the glycinanide ribonucleotide GAR -formyltransferase- and aminoimida-zole carboxamide ribonucleotide AICR - formyltransferase-mediated construction cf the purines 276 . The first antifolate used clinically was aminopterin 64...

Antisense Oligonucleotides It has

Been known that influenza viral mRNA synthesis is catalyzed by viral nucleocapsids, which consist of the individual viral RNAs vRNAs associated with four viral proteins the nucleocapsid protein NP and the three P proteins PB1, PB2, and PA . In a series of reports, Takaku et al. have demonstrated that antisense phosphodiester and phosphorothio-ate oligonucleotides that are complementary to the viral RNA polymerase PB1, PB2, PA and the nucleoprotein NP genes, specifically inhibited influenza A...

Molecular Basis Of Cancer Phenotypes

Cancer is a multistep process that requires the accumulation of multiple genetic mutations in a single cell that bestow features characteristic of a neoplastic cell. Typically, tumor cells differ from normal cells in that they exhibit uncontrolled growth. Because features that distinguish tumor from normal cells may be key to understanding neoplastic cell behavior and may ultimately lead to therapies that can target tumor cells, considerable effort has been directed at identifying the...

Monomeric Inhibitors of Influenza Hemagglutinin

Stachyflin Structure

In a series of publications, Bristol-Myers Squibb investigators have identified BMY-27709 28 as a new lead for the development of influenza fusion inhibitors 99-101 . In cell-based assays, this compound inhibited the growth of both HI and H2 subtypes of influenza A virus only when added at the early stage of infection with EC50 of 3-8 jlM 99 . However, it is inactive against H3 subtype 99 . To better understand the mechanism of action of the compound, 21...

Topo II Inhibitors

Structure Ametantrone Mitoxantrone

The two main classes of synthetic topo II inhibitors are the 9-anilinoacri-dines and the anthracenediones. The 9-anili-noacridine amsacrine evolved from work carried out by Cain and associates on antileukemic quinolinium-type agents 144 , which they suggested intercalated following initial minor groove binding of the remainder of the molecule 145 .A series of acridinium analogs 9-anilinoacridine 9-anilinoacridine anthracenedione Acridine Pyridoindole Indenoquinolone Bis...

Drug Chirality

Clomiphene Citrate Racemic

At least 25 are marketed as racemic mixtures 17 . The Unit ed States Pharmacopeia recognizes this in defining the chemical standards for many drugs 18 . Examples include Clomiphene citrate contains not less than 98.0 and not more than 102.0 of a mixture of the E - and 2 -geometric isomers of C20H28ClNOAC6H8O7, calculated on an anhydrous basis. It contains not less than 30.0 and not more than 50.0 of the 2-isomer. Doxepin Hydrochloride, USP Fig. 7.9 Doxepin...

K

Oseltamivir Cyclohexene Ring

Complex structure of NA and sialic acid dashes indicate H-bonding red and hydrophobic black interactions some active site residues are omitted for clarity . Reproduced with permission of Dr. C. U. Kim GileadSciences . See color insert. Figure 10.2. Complex structure of NA and sialic acid dashes indicate H-bonding red and hydrophobic black interactions some active site residues are omitted for clarity . Reproduced with permission of Dr. C. U. Kim GileadSciences . See color insert....

Short Capped Oligonucleotides To

Trastuzumab Diketopiperazine

Initiate influenza viral mRNA synthesis, the viral associated RNA-dependent RNA polymerase binds to the cap structure at the 5' ends of host cell RNA polymerase II transcripts and then a virally encoded endonucle-ase cleaves the capped 5'-termini to provide caps for the 5'-termini of the viral mRNAs and to serve as primers for transcription by the viral RNA-dependent RNA polymerase RNA transcriptase . The PB2 polymerase protein mediates both the binding and the endonu-cleolytic cleavage of...

Inhibitors of Picornaviral Proteases

The genome of HRV contains a single open reading frame that can be translated into a large polyprotein, which undergoes further processing by two vi-rally encoded proteases, designated 2A and 3C, to produce structural and functional proteins required for viral replication. In human rhinoviruses, the 2A protease separates the structural from the non-structural protein precursors, followed by the 3C protease, or its 3CD precursor, which carries out eight of the...

Cellular Picture of the lnfection

Once the virus is inside the body, it targets a certain type of cell called a T4 lymphocyte, a white blood cell that has a central role in regulating the immune system, specifically the CD4 helper T-cells 5 . After the virus entry to the T4 cell, it may remain latent until the lymphocyte is immunologically stimulated by a secondary infection. Then the virus bursts into action, reproducing itself so furiously that the new virus particles escaping from the cell riddle the cellular membrane with...

Recent Developments bis Analogs as Dual Topo 111 Inhibitors Because of the early

SAR suggesting a positive correlation between cytotoxic potency and the strength of ENsA. binding and because bis-intercalation would theoretically greatly increase DNA binding, many dimeric compounds designed as bis-in-tercalators were evaluated as anticancer drugs 134, 265 . However, the biological activities of these compounds were generally disappointing. The bis acridine 56 was considered for clinical trial 266 but had significant