Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

Uniportal VATS for Diagnosis and Staging in Non-Small Cell Lung Cancer (NSCLC).

Uniportal VATS has become an accepted approach in minimally invasive thoracic surgery since its first report for lobectomy in 2011. Since the initial restrictions in indications, it has been used in almost all procedures, from conventional lobectomies to sublobar resections, bronchial and vascular sleeve procedures and even tracheal and carinal resections. In addition to its use for treatment, it provides an excellent approach for suspicious solitary undiagnosed nodules after bronchoscopic or transthoracic image-guided biopsy. Uniportal VATS is also used as a surgical staging method in NSCLC due to its low invasiveness in terms of chest tube duration, hospital stay and postoperative pain. In this article, we review the evidence of uniportal VATS accuracy for NSCLC diagnosis and staging and provide technical details and recommendations for its safe performance for that purpose.

The techniques of uniportal video-assisted thoracoscopic surgery: lower lobectomies and lymphadenectomy.

Uniportal video-assisted thoracoscopic surgery (VATS) is probably the most successful single-incision approach worldwide, probably secondary to several specific circumstances: multiportal VATS was hardly getting his recognition in the thoracic surgeon's community; the extraordinary effort by his creators and believers for developing the technique and giving massive diffusion; the subjective feeling by surgeons who performed the approach about its benefits and advantages. Despite this, many efforts have focused on extending new indications and describing variations of the original intercostal uniportal VATS, but few quality papers have analyzed the real impact of the approach and its real advantages or disadvantages comparing to multiportal VATS. Thus, many surgeons still feel little confidence on the approach and reject his performance. With the aim of standardizing the approach and the technical aspects for non-experienced or beginners, the Uniportal VATS Interest Group (UVIG) of the European Society of Thoracic Surgery (ESTS) decided to set the basis for homogenization of the technique to cement the development of high-level evidence works that shed light on the real outcomes of uniportal compared to multiportal VATS. This article describes the main specific technical aspects while performing lower lobectomies and lymphadenectomy, which were described as the most suitable cases for initiating the learning curve.

Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization.

Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization priority. Marinomycin A is a member of a new class of bis-salicylate-containing polyene macrodiolides, which have potent antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity of the aryl ester through an intramolecular resonance-assisted hydrogen bond to provide an amide surrogate.