A unified strategy for the total syntheses of eribulin and a macrolactam analogue of halichondrin B.

A unified synthetic route for the total syntheses of eribulin and a macrolactam analog of halichondrin B is described. The key to the success of the current synthetic approach includes the employment of our reverse approach for the construction of cyclic ether structural motifs and a modified intramolecular cyclization reaction between alkyl iodide and aldehyde functionalities to establish the all-carbon macrocyclic framework of eribulin. These syntheses, together with our previous work on the total syntheses of halichondrin B and norhalichondrin B, demonstrate and validate the powerful reverse approach in the construction of cyclic ether structural motifs.

A Highly Convergent Total Synthesis of Norhalichondrin B.

A new synthetic strategy for the total synthesis of norhalichondrin B featuring a highly convergent approach and our recently disclosed reverse approach for the synthesis of cyclic ether structural motifs is disclosed. Resulting in the shortest route to norhalichondrin B disclosed thus far, the reported total synthesis was achieved through the synthesis of two almost equally complex fragments whose coupling and short elaboration sequence featured an essential epimerization of the C16 stereocenter occurring concurrently with a simple acid-induced deprotection, a tactic based on a prior study along the synthetic route. This unprecedented strategy within the halichondrin family of natural products could find practical application to the synthesis of other more or less complex natural or designed halichondrin analogues.

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.

A Reverse Approach to the Total Synthesis of Halichondrin B.

A new strategy is described for the total synthesis of halichondrin B featuring reversal of the sequential construction of a number of its cyclic ethers from the classical approach by instead forming C-O bonds first followed by C-C bond formation. Employing the Nicholas reaction to generate linear ethers as precursors for the total synthesis of halichondrin B and other members of the halichondrin and eribulin families of compounds, this novel approach provides new opportunities for the development of improved syntheses of these complex and valuable compounds. In this Article, we report the syntheses of defined fragments , , , and .

Design, Synthesis, and Biological Evaluation of Tubulysin Analogues, Linker-Drugs, and Antibody-Drug Conjugates, Insights into Structure-Activity Relationships, and Tubulysin-Tubulin Binding Derived from X-ray Crystallographic Analysis.

Molecular design, synthesis, and biological evaluation of tubulysin analogues, linker-drugs, and antibody-drug conjugates are described. Among the new discoveries reported is the identification of new potent analogues within the tubulysin family that carry a C11 alkyl ether substituent, rather than the usual ester structural motif at that position, a fact that endows the former with higher plasma stability than that of the latter. Also described herein are X-ray crystallographic analysis studies of two tubulin-tubulysin complexes formed within the α/β interface between two tubulin heterodimers and two highly potent tubulysin analogues, one of which exhibited a different binding mode to the one previously reported for tubulysin M.

Perspectives from nearly five decades of total synthesis of natural products and their analogues for biology and medicine.

Covering: 1970 to 2020By definition total synthesis is the art and science of making the molecules of living Nature in the laboratory, and by extension, their analogues. Although obvious, its application to the synthesis of molecules for biology and medicine was not always the purpose of total synthesis. In recent years, however, the field has acquired momentum as its power to reach higher molecular complexity and diversity is increasing, and as the demand for rare bioactive natural products and their analogues is expanding due to their recognised potential to facilitate biology and drug discovery and development.

The Role of Organic Synthesis in the Emergence and Development of Antibody-Drug Conjugates as Targeted Cancer Therapies.

With a number of antibody-drug conjugates (ADCs) approved for clinical use as targeted cancer therapies and numerous candidates in clinical trials, the field of ADCs is emerging as one of the frontiers in biomedical research, particularly in the area of cancer treatment. Chemists, biologists and clinicians, among other scientists, are partnering their expertise to improve their design, synthesis, efficacy and precision as they strive to advance this paradigm of personalized and targeted medicine to treat cancer patients more effectively and to expand its scope to other indications. Just as Alexander Fleming's penicillin, and the myriad other bioactive natural products that followed its discovery and success in the clinic, ignited a revolution in medicine after the Second World War, so did calicheamicin γ , and other highly potent naturally occurring antitumor agents, play a pivotal role in enabling the advent of this new paradigm of "biological-small molecule hybrid" medical intervention.

Total Synthesis in Search of Potent Antibody-Drug Conjugate Payloads. From the Fundamentals to the Translational.

The emergence and evolution of antibody-drug conjugates (ADCs) as targeted cancer therapies in recent years is a living example of the "magic bullet" concept of Paul Ehrlich, introduced by him more than a century ago. Consisting of three components, the antibody serving as the delivery system, the payload drug that kills the cancer cell, and the chemical linker through which the payload is attached to the antibody, ADCs represent a currently hotly pursued paradigm of targeted cancer therapies. While the needed monoclonal antibody falls in the domains of biology and biochemistry, the potent payload and the linker belong to the realm of chemistry.

Short Total Synthesis of Δ-Prostaglandin J and Related Prostaglandins. Design, Synthesis, and Biological Evaluation of Macrocyclic Δ-Prostaglandin J Analogues.

Comprised of a large collection of structurally diverse molecules, the prostaglandins exhibit a wide range of biological properties. Among them are Δ-prostaglandin J (Δ-PGJ) and Δ-prostaglandin J (Δ-PGJ), whose unusual structural motifs and potent cytotoxicities present unique opportunities for chemical and biological investigations. Herein, we report a short olefin-metathesis-based total synthesis of Δ-PGJ and its application to the construction of a series of designed analogues possessing monomeric, dimeric, trimeric, and tetrameric macrocyclic lactones consisting of units of this prostaglandin.

Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents.

An improved and enantioselective total synthesis of antibiotic CJ-16,264 through a practical kinetic resolution and an iodolactonization reaction to form the iodo pyrrolizidinone fragment of the molecule is described. A series of racemic and enantiopure analogues of CJ-16,264 was designed and synthesized through the developed synthetic technologies and tested against drug-resistant bacterial strains. These studies led to interesting structure-activity relationships and the identification of a number of simpler, and yet equipotent, or even more potent, antibacterial agents than the natural product, thereby setting the foundation for further investigations in the quest for new anti-infective drugs.

Streamlined Total Synthesis of Trioxacarcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxacarcin Analogues.

A streamlined total synthesis of the naturally occurring antitumor agents trioxacarcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthraquinones and chloro anthraquinones from simple ketone precursors and phenylselenyl chloride is also described.

Experimental Evolution of Diverse Strains as a Method for the Determination of Biochemical Mechanisms of Action for Novel Pyrrolizidinone Antibiotics.

The continuing rise of multidrug resistant pathogens has made it clear that in the absence of new antibiotics we are moving toward a "postantibiotic" world, in which even routine infections will become increasingly untreatable. There is a clear need for the development of new antibiotics with truly novel mechanisms of action to combat multidrug resistant pathogens. Experimental evolution to resistance can be a useful tactic for the characterization of the biochemical mechanism of action for antibiotics of interest.

A brief history of antibiotics and select advances in their synthesis.

The advent of modern antibiotics contributed enormously to the dramatic extension of human lifespan since their discovery by virtue of their lethal and selective action against pathogenic microbes. And yet despite our powerful arsenal of weapons against these pathogens, the war against them has not been won. And it may never be.

Total Synthesis of Δ(12) -Prostaglandin J3 : Evolution of Synthetic Strategies to a Streamlined Process.

The total synthesis of Δ(12) -prostaglandin J3 (Δ(12) -PGJ3 , 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji-Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C-H functionalization of cyclopentenes and related olefins was discovered.

Synthesis and Biological Investigation of Δ(12)-Prostaglandin J3 (Δ(12)-PGJ3) Analogues and Related Compounds.

A series of Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1.

Synthesis of a hexasaccharide partial sequence of hyaluronan for click chemistry and more.

In the present work, the synthesis of a hexasaccharide partial sequence of hyaluronan equipped with a terminal azido moiety is reported. This hexasaccharide can be used for the attachment on surfaces by means of click chemistry and after suitable deprotection for biophysical studies.

A novel approach to decrease sialic acid expression in cells by a C-3-modified N-acetylmannosamine.

Due to its position at the outermost of glycans, sialic acid is involved in a myriad of physiological and pathophysiological cell functions such as host-pathogen interactions, immune regulation, and tumor evasion. Inhibitors of cell surface sialylation could be a useful tool in cancer, immune, antibiotic, or antiviral therapy. In this work, four different C-3 modified N-acetylmannosamine analogs were tested as potential inhibitors of cell surface sialylation.

Hünlich base: (re)discovery, synthesis, and structure elucidation after a century.

After almost 100 years, the structure of the product of the reaction between 2,4-diaminotoluene and formaldehyde was elucidated: derivative 3, which we call the Hünlich base, was synthesized on a multigram scale and its enantiomers were easily separated in preparative amounts. Furthermore, transformation of the NH2 groups to the corresponding bis-iodides and bis-azides is presented. The latter was also used for desymmetrization by click chemistry.

Synthesis of ¹³C-labeled and functionalized Hyaluronan derivatives for biophysical studies and surface modifications.

A convergent synthesis of a tetrasaccharide partial sequence of (13)C-labeled Hyaluronan is presented. This tetrasaccharide can be used for biophysical studies as well as for surface modifications. Furthermore, tetrasaccharide 7 can be employed for the synthesis of additionally labeled higher oligomers of Hyaluronan on the basis of the presented methodology.

[Pediatric surgery 2.0].

New tools from the web are a complete breakthrough in management of information. The aim of this paper is to present different resources in a friendly way, with apps and examples in the different phases of the knowledge management for the paediatric surgeon: search, filter, reception, classification, sharing, collaborative work and publication. We are assisting to a real revolution on how to manage knowledge and information.

Potent small molecule Hedgehog agonists induce VEGF expression in vitro.

Here, we describe the synthesis, SAR studies as well as biological investigations of the known Hedgehog signaling agonist SAG and a small library of its analogues. The SAG and its derivatives were analyzed for their potency to activate the expression of the Hh target gene Gli1 in a reporter gene assay. By analyzing SAR important molecular descriptors for Gli1 activation have been identified.

[Retrospective evaluation of carcinoid tumors of the appendix in children].

Carcinoids of the appendix are rare in children. Usually diagnosed incidentally on histologic investigation following appendectomy for acute apendicitis. To investigate the significance of the diagnosis of appendiceal carcinoid tumors in children, we conducted a retrospective study in our institution.

[Cystic adenomatoid malformation pulmonary: are we able to foresee its evolution?].

The congenital pulmonary malformation are a rare entity in pediatric age. Between of them, the cystic adenomatoid malformation (MAQ) is the most ferquent entity, followed by pulmonary sequestration (SP) and the most rare broncogenic cyst. As a consequence of ultrasound and fetal magnetic resonance we are abble to diagnose earlier this patology.