Takushi Kaneko

Adriamycin(hydrazone)-antibody conjugates require internalization and intracellular acid hydrolysis for antitumor activity.

SummaryAdriamycin hydrazone (ADM-Hzn) immunoconjugates have previously been shown to exhibit antibody-directed antitumor activity in vitro and in vivo. In this report, the biological and biochemical properties of the mAb and linker were investigated. Conjugates prepared with two antibodies 5E9 [anti-(transferrin receptor)] and G28.1 (anti-CD37), (which internalize from the surface of target cells following binding) were more cytotoxic in vitro and had greater antitumor activity against Daudi B lymphoma tumor xenografts than a non-internalizing immunoconjugate prepared with mAb 2H7 (anti-CD20). In addition, the 13-acylhydrazone bond linking the drug to the mAb was labile at pH 5 and released unmodified ADM at a rapid rate (t1/2 = 2.5 h). Immunoconjugates prepared with an oxime linkage at the C-13 position were stable to acid and were not cytotoxic. These findings suggest that internalization of ADM-Hzn immunoconjugates and release of free ADM from the mAb in acidic intracellular compartments were important steps in the mechanism of action of ADM-Hzn immunoconjugates.

Pyripyropenes, novel ACAT inhibitors produced by Aspergillus fumigatus. III: Structure elucidation of pyripyropenes E to L

Eight new pyripyropenes, E to L, were isolated from the culture broth of Aspergillus fumigatus FO-1289-2501 selected as a higher producer by NTG mutation. Structural elucidation indicated that all the pyripyropenes have the same pyridino-alpha-pyrone sesquiterpene core as pyripyropenes A to D. Among them, pyripyropene L showed the most potent inhibition against acyl-CoA: cholesterol acyltransferase (ACAT) activity with an IC50 value of 0.27 microM in rat liver microsomes.

Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

Recent developments in the area of macrolide antibiotics

There have been exciting developments in the area of macrolide antibiotics recently. This activity largely stems from the discovery and development of a new class of agents called ketolides. They are more potent than erythromycin A and active against macrolide-resistant pathogens. At the same time, our knowledge of the mechanism of action of macrolides has been refined and resistance mechanisms have been elucidated. By employing new chemical methods and combinatorial biosynthesis, qualitatively different kinds of derivatives are being synthesised. Alternative non-infective uses for macrolide templates are also being explored. These areas are reviewed primarily in relation to 14-membered macrolides.

7.18 – Macrolide Antibiotics

Macrolide antibiotics such as erythromycin, clarithromycin, and azithromycin have been used widely to combat primarily respiratory diseases caused by Gram-positive pathogens and fastidious Gram-negative pathogens. The popularity of this class of antibiotics is largely due to their spectrum of activity and their relative safety. The second-generation macrolides, clarithromycin and azithromycin, are derived from erythromycin, and have a broader spectrum of activity and improved pharmacokinetic properties. Macrolide antibiotics inhibit bacterial protein synthesis by interfering with ribosome function, and details of the inhibitory mechanisms have been clarified by recent advances in the x-ray structure of the ribosome–macrolide complexes. The widespread use of these antibiotics had catalyzed the emergence of macrolide-resistant strains, especially among Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. In response to these resistant pathogens, third-generation macrolides, represented by the ketolide telithromycin, are being developed. These derivatives have increased affinity for the bacterial ribosome and a reduced propensity to be efflux pump substrates compared with the first- and second-generation macrolides. Discovery of telithromycin and its introduction into the market triggered a renewed interest in the chemistry of macrolide antibiotics in recent years. As a result, a large number of novel and potent analogs were synthesized and are under investigation. In this chapter, the major classes of macrolide antibiotics as well as the newer analogs are reviewed. Included are descriptions of their syntheses, their mechanism of action, resistance mechanisms, structure–activity relationship (SAR), and their pharmacokinetic and safety properties.

Chapter 17. New Antibacterials for Resistant Organisms

Publisher Summary This chapter focuses on new antibacterials for resistant organisms. The last decade of the 20th century brought with it vancomycin-resistant S. aureus . These glycopeptide intermediate resistant strains (GISA) may receive the most public attention of the resistant bacteria. The chapter focuses on new antibacterial agents reported in the recent past. New parenteral carbapenem, L-786,392, was reported to have excellent gram-positive activity in vitro . The compound was superior to imipenem in vivo , including efficacy in a vancomycin resistant enterococcal (VRE) thigh model. This is believed to be due to lower plasma clearance and the resulting improved pharmacokinetics. The compound has reduced immunotoxicity in monkeys compared to earlier compounds in the series. A comprehensive review of the chemistry, SAR and mechanism of action of quinolones is also discussed. Several late-stage clinical candidates continued to progress through clinical trials. Trovafloxacin and its iv companion, alatrofloxacin, gained US FDA approval and were launched in late January 1998. Recent developments related to glycylcyclines, macrolides, and oxazolidinones are also discussed in the chapter.

Identification and optimization of a new series of anti-tubercular quinazolinones.

A high throughput phenotypic screening against Mycobacterium smegmatis led us to the discovery of a new class of bacteriostatic, highly hydrophobic antitubercular quinazolinones that potently inhibited the in vitro growth of either extracellular or intramacrophagic M. tuberculosis (Mtb), via modulation of an unidentified but yet novel target. Optimization of the initial hit compound culminated in the identification of potent but poorly soluble Mtb growth inhibitors, three of which were progressed to in vivo efficacy studies. Despite nanomolar in vitro potency and attractive PK properties, none of these compounds was convincingly potent in our in vivo mouse tuberculosis models. This lack of efficacy may be linked to the poor drug-likeness of the test molecules and/or to the properties of the target.

Ring-mediated transformations of macrolide antibiotics

Ketene acetal intermediate 5 was synthesized and shown to be a useful intermediate in the synthesis of macrolide antibiotics. Its synthesis and subsequent substitution reactions are controlled by the macrocyclic ring system and the juxtaposition of functional groups. The ring-mediated reactions provided unique 13- and 14-membered macrolide templates different from those available biosynthetically.