Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect.

Antibody-drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, -acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs.

Evaluation of PNU-159682 antibody drug conjugates (ADCs).

PNU-159682 is a highly potent secondary metabolite of nemorubicin belonging to the anthracycline class of natural products. Due to its extremely high potency and only partially understood mechanism of action, it was deemed an interesting starting point for the development of a new suite of linker drugs for antibody drug conjugates (ADCs). Structure activity relationships were explored on the small molecule which led to six linker drugs being developed for conjugation to antibodies.

Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C-H Borylation.

Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan.

Mechanism, reactivity, and selectivity of nickel-catalyzed [4 + 4 + 2] cycloadditions of dienes and alkynes.

Density functional theory (DFT) calculations with B3LYP and M06 functionals elucidated the reactivities of alkynes and Z/E selectivity of cyclodecatriene products in the Ni-catalyzed [4 + 4 + 2] cycloadditions of dienes and alkynes. The Ni-mediated oxidative cyclization of butadienes determines the Z/E selectivity. Only the oxidative cyclization of one s-cis to one s-trans butadiene is facile and exergonic, leading to the observed 1Z,4Z,8E-cyclodecatriene product.

An approach to mimicking the sesquiterpene cyclase phase by nickel-promoted diene/alkyne cooligomerization.

Artificially mimicking the cyclase phase of terpene biosynthesis inspires the invention of new methodologies, since working with carbogenic frameworks containing minimal functionality limits the chemist's toolbox of synthetic strategies. For example, the construction of terpene skeletons from five-carbon building blocks would be an exciting pathway to mimic in the laboratory. Nature oligomerizes, cyclizes, and then oxidizes γ,γ-dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) to all of the known terpenes.

Cooperative catalysis by carbenes and Lewis acids in a highly stereoselective route to gamma-lactams.

Enzymes are a continuing source of inspiration for the design of new chemical reactions that proceed with efficiency, high selectivity and minimal waste. In many biochemical processes, different catalytic species, such as Lewis acids and bases, are involved in precisely orchestrated interactions to activate reactants simultaneously or sequentially. This type of 'cooperative catalysis', in which two or more catalytic cycles operate concurrently to achieve one overall transformation, has great potential in enhancing known reactivity and driving the development of new chemical reactions with high value.

Excision of hemivertebrae and wedge resection in the treatment of congenital scoliosis.

The results of anterior and posterior excision or wedge resection of a hemivertebra and arthrodesis of the spine were reviewed retrospectively for thirty-seven patients. The degree of correction that was obtained and maintained, the balance and alignment of the trunk, changes in pelvic obliquity, and associated complications were evaluated. The average age at the time of the operation was twelve years (range, six months to forty-two years).

Anterior lumbar fusion using a hybrid interbody graft. A preliminary radiographic report.

This is a radiographic report of 40 patients (20 men, 20 women) who underwent anterior lumbar interbody fusions (73 levels) utilizing a "hybrid" interbody graft composed of femoral cortical allograft (FCA) bone and iliac crest cancellous autograft bone. The average age at surgery was 38 years (range 17-64 years), and follow-up averaged 1.4 years (range 1.

Simultaneous combined anterior and posterior fusion. A review of its concept and 10 years of refinement of the technique: a solution for the patient with severe back and leg pain.

This paper reviews the principles, developments and concepts embodied in the experience gained over 10 years with simultaneous combined anterior and posterior fusion (SCAPF) of the spine in over 750 patients. The procedure was initially designed for the surgical treatment of failed post-discectomy syndromes. Indications have expanded due to increasing experience and the rapid, predictable fusion which accompanies this technique.

Osteonecrosis secondary to internal fixation.

Allergies to metals as a cause of failure of joint prostheses has historically been a controversial issue. Loosening of a prosthesis may be due to trauma, infection of the surrounding area, or a faulty implantation of the device. However, cases of loosening of the device do occur without any history of the above criteria.