Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody-drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado-trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first-generation ADCs have led to improvements in every aspect of this technology, i.e., the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.

Antibody-drug conjugates: an emerging concept in cancer therapy

Mechanisms of in situ activation for DNA-targeting antitumor agents.

Chromatographic enantioseparations, particularly resolution by high-performance liquid chromatography (HPLC), have advanced considerably in the past decade, and have become a practically useful method not only for determining their optical purity, but also for obtaining optical isomers. The preparation of a chiral stationary phase (CSP) capable of effective chiral recognition is the key to this separation technique. We have found that polysaccharide derivatives, particularly cellulose esters and phenylcarbamate derivatives of cellulose and amylose, are very effective CSPs, and can resolve a wide range of racemates, including drugs. A variety of polysaccharides derivatives involving tribenzoates and tris(phenylcarbamates) of cellulose and amylose were prepared and their chiral recognition abilities were evaluated as CSPs in HPLC. The chiral recognition and resolving ability of the derivatives depend greatly on the substituents introduced on the phenyl moieties. The introduction of electron-donating or elec...

Chiral Discrimination on Polysaccharides Derivatives

Biologically relevant chemical reactions of N7-alkylguanine residues in DNA.

Synthetic DNA minor groove-binding drugs.

A detailed study of the DNA alkylation properties of (+)-duocarmycin SA, ent-(-)-duocarmycin SA, and (+)- and ent-(-)-N-BOC-DSA (2) is described, and the development of a model that accommodates the offset AT-rich adenine N3 alkylation selectivity of the enantiomeric agents is presented

(+)- and ent-(-)-Duocarmycin SA and (+)- and ent-(-)-N-BOC-DSA DNA Alkylation Properties.Alkylation Site Models That Accommodate the Offset AT-Rich Adenine N3 Alkylation Selectivity of the Enantiomeric Agents

A concise and improved synthesis of 11, the immediate precursor to N-BOC-CBI and related analogues of CC-1065 incorporating the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one alkylation subunit, is detailed based on a direct 5-exo-trig aryl radical-alkene cyclization for 3-hydroxymethylindoline generation

An improved synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI): a simplified analog of the CC-1065 alkylation subunit

CBI-TMI: Synthesis and Evaluation of a Key Analog of the Duocarmycins. Validation of a Direct Relationship between Chemical Solvolytic Stability and Cytotoxic Potency and Confirmation of the Structural Features Responsible for the Distinguishing Behavior of Enantiomeric Pairs of Agents

Molecular basis for sequence selective DNA alkylation by (+)- and ent-(-)-CC-1065 and related agents: alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity.

Weiya Yun

Papers

(+)- and ent-(-)-Duocarmycin SA and (+)- and ent-(-)-N-BOC-DSA DNA Alkylation Properties.Alkylation Site Models That Accommodate the Offset AT-Rich Adenine N3 Alkylation Selectivity of the Enantiomeric Agents

An improved synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI): a simplified analog of the CC-1065 alkylation subunit

CBI-TMI: Synthesis and Evaluation of a Key Analog of the Duocarmycins. Validation of a Direct Relationship between Chemical Solvolytic Stability and Cytotoxic Potency and Confirmation of the Structural Features Responsible for the Distinguishing Behavior of Enantiomeric Pairs of Agents

Molecular basis for sequence selective DNA alkylation by (+)- and ent-(-)-CC-1065 and related agents: alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity.

1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogs of CC-1065 and the duocarmycins: synthesis and evaluation.