Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/1521-3773%2820010601%2940%3A11%3C2004%3A%3AAID-ANIE2004%3E3.0.CO%3B2-5

Click Chemistry: Diverse Chemical Function from a Few Good Reactions.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

/pdf/molecular-definitions-of-cell-death-subroutines-q5g428rlyi.pdf

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

/pdf/targeting-autophagy-in-cancer-2pjcn0h04a.pdf

Targeting autophagy in cancer

The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies...

/pdf/mammalian-nicotinic-acetylcholine-receptors-from-structure-1woeprh7qg.pdf

Mammalian nicotinic acetylcholine receptors: from structure to function.

Observations on the Preparation of 2β-Hydroxy-19-oxoandrost-4-ene-3,7-dione (I). Synthesis of a 2β,19-Oxaandrost-4-ene-3,17-dione (II).

In a recent article by Norris and colleagues, published in high-impact J Clin Invest (1), the authors investigated the potential role of androgen receptor (AR) antagonism and the efficacy of cytochrome P450 17A1 (hereafter called CYP17) inhibitors in prostate cancer models.

/pdf/androgen-receptor-antagonism-and-impact-on-inhibitors-of-2rxepxiw2h.pdf

Androgen receptor antagonism and impact on inhibitors of androgen synthesis in prostate cancer therapy.

Described are steroidal C- 17 benzoazoles, pyrimidinoazoles (azabenzoazoles) and diazines. Methods for their synthesis are also described, which include methods having a step of nucleophilic vinylic addition-elimination substitution reaction of 3ss-acetoxy-17- chloro-16-formylandrosta-5,16-diene or analogs thereof and benzoazole or pyrimidinoazole nucleophiles and methods having a palladium catalyzed cross-coupling reaction of 17- iodoandrosta-5,16-dien-3ss-ol or analogs thereof with tributylstannyl diazines. The compounds are potent inhibitors of human CYP 17 enzyme as well as potent antagonists of both wild type and mutant androgen receptors (AR). The compounds are useful for the treatment of human prostate cancer.

Steroidal c- 17 benzoazoles

Salinization Dramatically Enhance the Anti-Prostate Cancer Efficacies of AR/AR-V7 and Mnk1/2 Molecular Glue Degraders, Galeterone and VNPP433-3β Which Outperform Docetaxel and Enzalutamide in CRPC CWR22Rv1 Xenograft Mouse Model.

Nucleophilic Vinylic “Addition‐Elimination” Substitution Reaction of 3. beta.‐Acetoxy‐17‐chloro‐16‐formylandrosta‐5,16‐diene: A Novel and General Route to 17‐Substituted Steroids. Part 1. Synthesis of Novel 17‐Azolyl‐δ16 Steroids; Inhibitors of 17α‐Hydroxylase/17, 20‐Lyase (17α‐Lyase).

Vincent C. O. Njar

Papers

Observations on the Preparation of 2β-Hydroxy-19-oxoandrost-4-ene-3,7-dione (I). Synthesis of a 2β,19-Oxaandrost-4-ene-3,17-dione (II).

Androgen receptor antagonism and impact on inhibitors of androgen synthesis in prostate cancer therapy.

Steroidal c- 17 benzoazoles

Salinization Dramatically Enhance the Anti-Prostate Cancer Efficacies of AR/AR-V7 and Mnk1/2 Molecular Glue Degraders, Galeterone and VNPP433-3β Which Outperform Docetaxel and Enzalutamide in CRPC CWR22Rv1 Xenograft Mouse Model.