Heterocyclic Ketene Aminals: Scaffolds for Heterocycle Molecular Diversity

Abstract

Metastasis remains a leading cause of morbidity and mortality from solid tumors. Lack of comprehensive systems to study the progression of metastasis contributes to the low success of treatment. We developed a novel three‐dimensional in vitro reconstructed metastasis (rMet) model that incorporates extracellular matrix (ECM) elements characteristic of the primary (breast, prostate, or lung) and metastatic (bone marrow, BM) sites. A cytokine‐rich liquid interphase separates the primary and distant sites, further recapitulating circulation. Similar to main events underlying the metastatic cascade, the rMet model fractionated human tumor cell lines into sub‐populations with distinct invasive and migratory abilities: (i) a primary tumor‐like fraction mainly consisting of non‐migratory spheroids; (ii) an invasive fraction that invaded through the primary tumor ECM, but failed to acquire anchorage‐independence and reach the BM; and (iii) a highly migratory BM‐colonizing population that invaded the primary ECM, survived in the “circulation‐like” media, and successfully invaded and proliferated within BM ECM. BM‐colonizing fractions successfully established metastatic bone lesions in vivo, whereas the tumor‐like spheroids failed to engraft the bones, showing the ability of the rMet model to faithfully select for highly aggressive sub‐populations with a propensity to colonize a metastatic site. By applying the rMet model to study real‐time ECM remodeling, we show that tumor cells secrete collagenolytic enzymes for invading the primary site ECM but not for entering the BM ECM, indicating possible differences in ECM remodeling mechanisms at primary tumor versus metastatic sites.

The Resurgence of the Highly Ylidic N‐Heterocyclic Olefins as a New Class of Organocatalysts

“…NHOs have been regarded amongst the most ylidic alkenes with localized electron density on the exocyclic α‐carbon (C α ) up to −0.44, making it even more nucleophilic than the nitrogen centers on the same molecule . This interesting feature of NHOs offers multinucleophilic reactivity over the ketene aminal framework …”

“…During the last three decades, there have been numerous investigations on the synthetic utilities of NHOs as enaminic substrates in nucleophilic addition and substitution reactions . NHOs typically react with azides, nitrile oxides, and nitrile imines to give access to the corresponding triazoles, isoxazoles, and pyrazoles . They can also be used as dienophiles in inverse‐electron‐demand Diels–Alder and other cycloaddition reactions .…”

“…NHOs typically react with azides, nitrile oxides, and nitrile imines to give access to the corresponding triazoles, isoxazoles, and pyrazoles . They can also be used as dienophiles in inverse‐electron‐demand Diels–Alder and other cycloaddition reactions . Due to the strong nucleophilicity of the α‐carbon, NHOs are often stronger Lewis bases than their parent NHCs, leading to several applications of NHOs as end‐on ligands in transition metal coordination and catalysis,– as well as stabilization of the metalloid boron and silicon in borenium ions, and silylenes .…”

Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)—The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules

“…MCRs have been also applied in polymer [74], nucleoside [75] and carbohydrate [76] chemistry. Main field of application remains the production of heterocyclic compounds and many natural products by means of MCR [38,[77][78][79][80][81][82][83][84][85][86][87][88][89], leading directly towards drug design and discovery [90][91][92][93][94]. Scheme 9 presents a current brief of well-known multicomponent reactions [35,40,9,[95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110].…”

“…Scifinder) about the target products and intermediates of the synthesis plan. With respect to 1: New and in particular novel MCRs [38,45,61,82,83,114,115,[176][177][178][179][180][181][182] are the basis and guarantee for high diversity and therewith the capacity to produce many structurally-different compounds. A method has been found to design MCRs going from libraries of compounds to libraries of reactions [180].…”