ABSTRACT
ADCs based on the natural product maytansine have been successfully employed clinically. In a previous report, ADCs based on hydrophilic non-cell permeable maytansinoids was presented. The authors in this report further explore the maytansine scaffold to develop tubulin inhibitors capable of cell permeation. The research resulted in amino-benzoyl-maytansinoid payloads that were further elaborated with linkers for conjugating to antibodies. This approach was applied to MUC16 tumor targeting antibodies for ovarian cancers. A positive control ADC was evaluated alongside the amino-benzoyl-maytansinoid ADC and the efficacy observed was equivalent while the isotype control ADCs had no effect.
Subject(s)
Immunoconjugates/metabolism , Maytansine/chemistry , Tubulin Modulators/chemistry , Animals , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Immunoconjugates/chemistry , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Maytansine/metabolism , Mice, SCID , Neoplasms/drug therapy , Neoplasms/pathology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/metabolismABSTRACT
Bromine induced lactamization of vinyl acetohydroxamates facilitated syntheses of monocyclic ß-lactams suitable for incorporation of a thiomethyl and extended functionality at the C(4) position. Elaboration of the resulting substituted N-hydroxy-2-azetidinones allowed incorporation of functionalized α-amino substituents appropriate for enhancement of antibiotic activity. Evaluation of antibacterial activity against a panel of Gram-positive and Gram-negative bacteria revealed structure-activity relationships (SAR) and identification of potent new monobactam antibiotics. The corresponding bis-catechol conjugate, 42, has excellent activity against Gram-negative bacteria including carbapenemase and carbacephalosporinase producing strains of Acinetobacter baumannii, which have been listed by the WHO as being of critical concern worldwide.
Subject(s)
Gram-Negative Bacteria/drug effects , Monobactams/chemistry , beta-Lactams/chemistry , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/enzymology , Bacterial Proteins , Catechols/pharmacology , Methods , Microbial Sensitivity Tests , Monobactams/chemical synthesis , Structure-Activity Relationship , beta-LactamasesABSTRACT
The synthesis of a small library of N-sulfonyloxy-2-azetidinones is reported and the preliminary results of the investigation of the biological activity of these molecules are discussed. These new multi-electrophilic ß-lactams ('electrophilic bombs') display unexpected selectivity in their antibacterial activity and ß-lactamase inhibitory activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , beta-Lactamase Inhibitors/chemical synthesis , beta-Lactamases/chemistry , beta-Lactams/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Kinetics , Structure-Activity Relationship , beta-Lactamase Inhibitors/chemistry , beta-Lactamase Inhibitors/pharmacology , beta-Lactamases/metabolism , beta-Lactams/chemical synthesis , beta-Lactams/pharmacologyABSTRACT
This review describes the use of nitroso Diels-Alder reactions for the functionalization of complex diene-containing natural products in order to generate libraries of compounds with potential biological activity. The application of this methodology to the structural modification of a series of natural products (thebaine, steroidal dienes, rapamycin, leucomycin, colchicine, isocolchicine and piperine) is discussed using relevant examples from the literature from 1973 onwards. The biological activity of the resulting compounds is also discussed. Additional comments are provided that evaluate the methodology as a useful tool in organic, bioorganic and medicinal chemistry.
Subject(s)
Biological Products/chemistry , Biological Products/chemical synthesis , Cycloaddition Reaction/methods , Nitroso Compounds/chemistry , Polyenes/chemistryABSTRACT
Herein two new and concise synthetic approaches for making an unsaturated bicyclic oxamazin core are reported. The first involves the use of an intramolecular Diels-Alder reaction to form both of the fused rings in one step. The second approach incorporates ring-closing olefin metathesis in the final step to form the second fused ring of the core. The scope of the second approach was also expanded further to afford larger ringed bicyclic systems.
Subject(s)
Alkenes/chemistry , beta-Lactams/chemical synthesis , Combinatorial Chemistry Techniques , Cyclization , Cycloaddition Reaction , Molecular Structure , Stereoisomerism , beta-Lactams/chemistryABSTRACT
Nitrosocarbonyl intermediates undergo ene reactions with allylic alcohols, affording regioisomeric adducts in fair yields. Nitrosocarbonyl benzene reacts with 3-methyl-2-buten-1-ol and follows a Markovnikov orientation and abstracts preferentially the twix hydrogens over the lone ones. With the more sterically demanding nitrosocarbonyl mesitylene and anthracene, the Markovnikov directing effect is relieved and lone abstraction is observed, affording the 5-hydroxy-isoxazolidines that serve as synthons for the preparation of N,O-nucleoside analogues according to the Vorbrüggen protocol.
