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.


 Introduction: Breast cancer remains a major concern as the second leading cause of cancer-related death in women in the United States and the most frequently diagnosed cancer in women globally. Among all the subtypes, triple negative breast cancer (TNBC) is highly resilient and eludes currently available treatment modalities. This study describes the mechanism of action of VNLG-152R in inhibiting TNBC tumor growth.
 Methods: TNBC cell lines MDA-MB-231 and MDA-MB-468 originated from TNBC patients of Caucasian American and African American descend, respectively, were challenged with VNLG-152R in vitro. The mechanism of action was studied by immunoblotting key proteins, proteasomal degradation assay of Mnk1/2 and transcriptome analysis by RNA-seq. The therapeutic potential of VNLG-152R is demonstrated in NRG mice bearing either MDA-MB-231 or MDA-MB-468 tumor xenografts.
 Results: We report for the first time, that, VNLG-152R significantly upregulates Synoviolin (SYVN1) in TNBC cell lines MDA-MB-231 and MDA-MB-468 with concomitant degradation of Mnk1/2. SYVN1 is a known E3-ubiquitin ligase and it ubiquitinates its target proteins, rendering them to proteasomal degradation. However, there was no significant change in Mnk1/2 levels upon treatment with VNLG-152R in presence of SYVN1 inhibitor LS102. A similar result is obtained upon siRNA knockdown of SYVN1. Subsequently, the decreased level of Mnk1/2 diminished the phosphorylation of eIF4E with a concurrent decrease in levels of eIF4E-validated downstream targets, Bcl-2 and Cyclin D1, resulting in tumor growth inhibition. Inhibition of proteasomal degradation by MG-132 prior to treating cells with VNLG-152R further supports that VNLG-152R promotes SYVN1-mediated ubiquitin-proteasomal degradation of Mnk1/2. Further, RNA-seq and Gene Set Enrichment Analysis (GSEA) of differentially expressed genes demonstrate inhibition of mTORC1 (mammalian target of rapamycin complex 1) and NUP153 (Nucleoporin 153) pathways and activation of p53 pathway thereby inhibiting tumor progression. Finally, oral administration of VNLG-152R to mice bearing tumor xenografts of either MDA-MB-231 or MDA-MB-468 significantly inhibited tumor growth and resulted in 87% and 80% tumor growth inhibition, respectively, without apparent host toxicity. Immunoblots of tumor tissue further demonstrate elevated levels of SYVN1 and decreased Mnk1/2 and p-eIF4E, which further confirms the role of SYVN1-mediated proteasomal degradation of Mnk1/2 in inhibiting TNBC tumor growth by VNLG-152R.
 Conclusion: As VNLG-152R potently inhibits development and progression of TNBC of different origins by upregulating E3 ubiquitin ligase SYVN1 leading to ubiquitination and proteasomal degradation of Mnk1/2 thereby decreased oncogenic phosphorylation of eIF4E by Mnk1/2, VNLG-152R could potentially be developed for the treatment of TNBC, irrespective of racial origin.
 Citation Format: Elizabeth Thomas, Retheesh S. Thankan, Puranik Purushottamachar, Vincent C. Njar. Mechanistic studies on VNLG-152R-mediated tumor inhibition of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB235.

Abstract LB235: Mechanistic studies on VNLG-152R-mediated tumor inhibition of triple negative breast cancer

SYNTHESES OF (15α-2H)-, (15β-2H)-, AND (15-2H2)PROGESTERONE

The stereospecific synthesis of the novel 6β,7β- and 6α, 7α-aziridinoandrost-4-ene-3,17-dione 21 and 23 has been accomplished by treatment of vicinal azidohydrins 19 and 20 respectively with triphenylphosphane. Several related compounds (fused steroidal oxiranes, azidohydrins and an azide) were also synthesized. Reaction of (E)-6-hydroxyiminoandrost-4-ene-3β,17β-diol 2 with lithium aluminium hydride (LAH) gave, respectively, 5β,6β- and 5α,6α-aziridinoandrostane-3β,17β-diol 5 and 6. Although the 6,7-aziridines and their N-derivatives are poor inhibitors of human placental microsomal aromatase, most of the other compounds are modest inhibitors, while 7α-acetoxy-6β-azidoandrost-4-ene-3,17-dione 24 is a potent inhibitor of the enzyme (IC50-value = 0.40 µ mol dm–3).

Synthesis of 6α,7α‐ and 6β,7β‐Aziridinoandrost‐4‐ ene‐3,17‐diones and Related Compounds: Potential Aromatase Inhibitors.

Retinoic acid metabolism blocking agents (RAMBAs). The RAMBAs may be used for treatment of cancer, including breast and prostate cancers. Methods for preparing novel retinamide RAMBAs. The methods include reacting RAMBAs with terminal polar carboxylic acid group with a variety of amines in the presence of suitable coupling reagents. The retinamide RAMBAs are potent inhibitors of the growth of prostate and breast cancer cells and may be useful for the treatment of these diseases in humans.

Retinamide and uses thereof

Nonsteroid and steroid compounds that cause down-regulation of the androgen receptor (AR), both full length and splice variant, induce apoptosis and inhibit proliferation of inhibiting proliferation and migration of androgen sensitive cancer cells. The steroid compounds and nonsteroid compounds may be agents for the prevention and/or treatment of cancer, including prostate cancer, castration resistant prostate cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, benign prostatic hyperplasia (BPH), Kennedy's disease, androgenetic alopecia, breast cancer, androgen-insensitive syndrome, and spinal and bulbar muscular atrophy.

Vincent C. O. Njar

Papers

Abstract LB235: Mechanistic studies on VNLG-152R-mediated tumor inhibition of triple negative breast cancer

SYNTHESES OF (15α-2H)-, (15β-2H)-, AND (15-2H2)PROGESTERONE

Synthesis of 6α,7α‐ and 6β,7β‐Aziridinoandrost‐4‐ ene‐3,17‐diones and Related Compounds: Potential Aromatase Inhibitors.

Retinamide and uses thereof

Steroidal compounds with potent androgen receptor down-regulation and anti prostate cancer activity