Carbon-Centered Reactivity in Carbodiphosphorane-Based Ligands Allowing for Redox-Non-Innocent Ligand/Ligand Dual Bond-Activation.

A pronounced nucleophilicity in combination with a distinct redox non-innocence is a unique feature of a coordinated ligand, which in the current case, leads to unprecedented carbon-centered reactivity patterns: A carbodiphosphorane-based (CDP) pincer-type rhodium complex allows to cleave two C-Cl-bonds of geminal dichlorides via two consecutive SN2-type oxidative additions resulting in the formation of a stabilized carbene fragment. In the presence of a suitable reductant the carbene fragment can even be converted into olefines or hydrodehalogenation products in a catalytic reaction. The developed method can also be used to convert chlorofluorocarbons (CFCs) such as CH2ClF to fluoromethane and methane.

Stage-specific function of sphingolipid synthases in African trypanosomes.

Unlabelled: The protozoan parasite is the only known eukaryote capable of synthesizing the three main phosphosphingolipids: sphingomyelin (SM), inositol phosphorylceramide (IPC), and ethanolamine phosphorylceramide (EPC). It has four paralogous genes encoding sphingolipid synthases (). TbSLS1 is a dedicated IPC synthase, TbSLS2 is a dedicated EPC synthase, and TbSLS3 and TbSLS4 are bifunctional SM/EPC synthases.

Synthesis and Enzymatic Evaluation of a Small Library of Substituted Phenylsulfonamido-Alkyl Sulfamates towards Carbonic Anhydrase II.

A small library of 79 substituted phenylsulfonamidoalkyl sulfamates, -, was synthesized starting from arylsulfonyl chlorides and amino alcohols with different numbers of methylene groups between the hydroxyl and amino moieties yielding intermediates -, followed by the reaction of the latter with sulfamoyl chloride. All compounds were screened for their inhibitory activity on bovine carbonic anhydrase II. Compounds - showed no inhibition of the enzyme, in contrast to sulfamates -.

Diethoxyphosphoryloxy-oleanolic acid is a nanomolar-inhibitor of butyrylcholinesterase.

A series of new betulin, lupeol, erythrodiol, and oleanolic acid phosphoryloxy- and furoyloxy-derivatives has been synthesized and their structure was confirmed by NMR spectroscopy. Synthesized compounds were subjected to Ellman's assays to determine their ability to inhibit the enzymes AChE and BChE. Among them, diethoxyphosphoryloxy-oleanolic acid inhibited BChE with a value of 99%, thereby acting as a mixed-type inhibitor holding very low K values of Ki = 6.

An asiatic acid derived trisulfamate acts as a nanomolar inhibitor of human carbonic anhydrase VA.

This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (hCA). Oleanolic acid (1), maslinic acid (2), betulinic acid (3), platanic acid (4), and asiatic acid (5) were chosen as representative triterpenoids for evaluation. The synthesis involved acetylation of parent triterpenoic acids 1-5, followed by sequential reactions with oxalyl chloride and benzylamine, de-acetylation of the amides, and subsequent treatment with sodium hydride and sulfamoyl chloride, leading to the formation of final compounds 21-25.

Inhibitory properties of quinopimaric acid derivatives towards cholinesterases.

A series of new diterpene quinopimaric acid derivatives modified at the hydroxyl group with different pharmacophore fragments has been synthesised and their (along with previously obtained compounds) inhibitory properties towards cholinesterases were studied. Thereby an indole-3-acetyl derivative and a propargyl substituted compound were shown to be excellent and acetylcholinesterase-selective inhibitors. Both compounds inhibited the enzyme as a mixed type inhibitor, and K values of 0.

Developing an Amide-Spacered Triterpenoid Rhodamine Hybrid of Nano-Molar Cytotoxicity Combined with Excellent Tumor Cell/Non-Tumor Cell Selectivity.

Asiatic acid, a pentacyclic triterpene, was converted into a series of piperazinyl, homopiperazinyl, and 1,5-diazocinyl spacered rhodamine conjugates, differing in the type of spacer and the substitution pattern on the rhodamine moiety of the hybrids. The compounds were tested for cytotoxic activity in SRB assays and compound , holding an EC of 0.8 nM, was the most cytotoxic compound of this series, but compound (containing a ring expanded 1,5-diazocinyl moiety and -propyl substituents on the rhodamine) was the most selective compound exhibiting a selectivity factor of almost 190 while retaining high cytotoxicity (EC = 1.

Targeted theranostics: Near-infrared triterpenoic acid-rhodamine conjugates as prerequisites for precise cancer diagnosis and therapy.

Pentacyclic triterpenoic acids have shown excellent potential as starting materials for the synthesis of highly cytotoxic agents with significantly reduced toxicity for non-malignant cells. This study focuses on the development of triterpenoic acid-rhodamine conjugates with fluorescence shifted to the near-infrared (NIR) region for theranostic applications in cancer research. Spectral analysis revealed emission wavelengths around λ = 760 nm, enabling stronger signals and deeper tissue penetration.

The Finally Rewarding Search for A Cytotoxic Isosteviol Derivative.

Acid hydrolysis of stevioside resulted in a 63% yield of isosteviol (), which served as a starting material for the preparation of numerous amides. These compounds were tested for cytotoxic activity, employing a panel of human tumor cell lines, and almost all amides were found to be non-cytotoxic. Only the combination of isosteviol, a (homo)-piperazinyl spacer and rhodamine B or rhodamine 101 unit proved to be particularly suitable.

Mitochondria-Targeting 1,5-Diazacyclooctane-Spacered Triterpene Rhodamine Conjugates Exhibit Cytotoxicity at Sub-Nanomolar Concentration against Breast Cancer Cells.

1,5-Diazacyclooctane was prepared by a simple synthetic sequence and coupled to pentacyclic triterpenoic acids oleanolic acid, ursolic acid, betulinic acid, platanic acid, and asiatic acid; these amides were activated with oxalyl chloride and reacted with rhodamine B or rhodamine 101 to yield conjugates. The conjugates were screened in SRB assays with various human breast cancer cell lines (MDA-MB-231, HS578T, MCF-7, and T47D) and found to exert cytotoxic activity even at a low concentration. Therefore, for an asiatic acid rhodamine 101 conjugate (28), an IC = 0.

Acetylcholinesterase Inhibitory Activity of Modified Lupane, Oleanane, and Ursane A-seco-Triterpenoids.

A series of new lupane, ursane, and oleanane type triterpenic A-seco-derivatives containing bromo-, azido-, alkyne-, 1H-tetrazol-5-yl-, 5-methyloxazol-2-yl-, N-(4-(4-methylpiperazin-1-yl)but-2-yn-1-yl), and a carbonyl group at C2, C24, C28, C30 positions has been synthesized. The bioactivity was evaluated by Ellman's method, and the results showed that most of the compounds displayed moderate acetylcholinesterase inhibitory activities in vitro. Among them, A-seco-derivatives of 28-oxo-allobetuline and betulinic acid with bromo- and azido-groups exhibited the most potent inhibitory activity against AChE.

A Large-Scale, Multiplayer Virtual Reality Deployment: A Novel Approach to Distance Education in Human Anatomy.

Unlabelled: The arrival of COVID-19 restrictions and the increasing demand of online instruction options posed challenges to education communities worldwide, especially in human anatomy. In response, Colorado State University developed and deployed an 8-week-long large-scale virtual reality (VR) course to supplement online human anatomy instruction. Students ( = 75) received a VR-capable laptop and head-mounted display and participated in weekly synchronous group laboratory sessions with instructors.

Asiatic acid as a leading structure for derivatives combining sub-nanomolar cytotoxicity, high selectivity, and the ability to overcome drug resistance in human preclinical tumor models.

Amides and rhodamine B conjugates of different pentacyclic triterpene acids have been shown outstanding cytotoxicity for human tumor cells. Starting from asiatic acid, a new rhodamine B hybrid has been synthesized, and its cytotoxic activity was investigated employing several human tumor cell lines (A375 (melanoma), HT29 (colorectal carcinoma), MCF7 (breast adenocarcinoma), A2780 (ovarian carcinoma), HeLa (cervical carcinoma), (NIH 3T3 (non-malignant murine fibroblasts). For these conjugates of this kind it has been established that the spacer attached to the carboxyl group at ring E governs the magnitude of the cytotoxicity.

Small Structural Differences Govern the Carbonic Anhydrase II Inhibition Activity of Cytotoxic Triterpene Acetazolamide Conjugates.

Acetylated triterpenoids betulin, oleanolic acid, ursolic acid, and glycyrrhetinic acid were converted into their succinyl-spacered acetazolamide conjugates. These conjugates were screened for their inhibitory activity onto carbonic anhydrase II and their cytotoxicity employing several human tumor cell lines and non-malignant fibroblasts. As a result, the best inhibitors were derived from betulin and glycyrrhetinic acid while those derived from ursolic or oleanolic acid were significantly weaker inhibitors but also of diminished cytotoxicity.

New amides derived from sclareolide as anticholinesterase agents.

A series of 25 amides (15 new) derived from (3aR)-(+)-sclareolide were prepared and subjected to Ellman's assay to determine their efficacies as inhibitors for AChE or BuChE. Five amides (9, 13, 14, 15 and 17) caused inhibition of one of the enzymes greater than 60%; thereby those that inhibited BuChE were more active than positive control galantamine, and they showed better K values (1.07 to 8.

Synthesis and In Silico Docking Study towards M-Pro of Novel Heterocyclic Compounds Derived from Pyrazolopyrimidinone as Putative SARS-CoV-2 Inhibitors.

In addition to vaccines, antiviral drugs are essential in order to suppress COVID-19. Although some inhibitor candidates have been determined to target the SARS-CoV-2 protein, there is still an urgent need to continue researching novel inhibitors of the SARS-CoV-2 main protease 'Omicron P132H', a protein that has recently been discovered. In the present study, in the search for therapeutic alternatives to treat COVID-19 and its recent variants, we conducted a structure-based virtual screening using docking studies for a new series of pyrazolo[3,4-]pyrimidin-4(5)-one derivatives -, which were synthesized from the condensation reaction of pyrazolopyrimidinone-hydrazide () with a series of electrophiles.

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives.

The synthesis and biological evaluation of novel guanidino sugars as isonucleoside analogs is described. 5-Guanidino xylofuranoses containing 3-O-saturated/unsaturated hydrocarbon or aromatic-containing moieties were accessed from 5-azido xylofuranoses via reduction followed by guanidinylation with N,N'-bis(tert-butoxycarbonyl)-N''-triflylguanidine. Molecules comprising novel types of isonucleosidic structures including 5-guanidino 3-O-methyl-branched N-benzyltriazole isonucleosides and a guanidinomethyltriazole 3'-O-dodecyl xylofuranos-5'-yl isonucleoside were accessed.

Rhodamine 101 Conjugates of Triterpenoic Amides Are of Comparable Cytotoxicity as Their Rhodamine B Analogs.

Pentacyclic triterpenoic acids (betulinic, oleanolic, ursolic, and platanic acid) were selected and subjected to acetylation followed by the formation of amides derived from either piperazine or homopiperazine. These amides were coupled with either rhodamine B or rhodamine 101. All of these compounds were screened for their cytotoxic activity in SRB assays.

Fetal Tissue-Derived Mast Cells (MC) as Experimental Surrogate for In Vivo Connective Tissue MC.

Bone-marrow-derived mast cells are matured from bone marrow cells in medium containing 20% fetal calf serum (FCS), interleukin (IL)-3 and stem-cell factor (SCF) and are used as in vitro models to study mast cells (MC) and their role in health and disease. In vivo, however, BM-derived hematopoietic stem cells account for only a fraction of MC; the majority of MC in vivo are and remain tissue resident. In this study we established a side-by-side culture with BMMC, fetal skin MC (FSMC) or fetal liver MC (FLMC) for comparative studies to identify the best surrogates for mature connective tissue MC (CTMC).

PHLPP1 deletion restores pancreatic β-cell survival and normoglycemia in the db/db mouse model of obesity-associated diabetes.

The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of β-cell survival and function in diabetes. Their upregulation and activation in β-cells under conditions of both type 1 and type 2 diabetes directly correlates with β-cell failure; β-cell death and loss of insulin secretory function through disturbance of cell survival control mechanisms. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1 constituting a regulatory triangle loop to control β-cell apoptosis.

N-methylated diazabicyclo[3.2.2]nonane substituted triterpenoic acids are excellent, hyperbolic and selective inhibitors for butyrylcholinesterase.

Triterpenoic acids (oleanolic, ursolic, betulinic, platanic and glycyrrhetinic acid) were acetylated and coupled with 1,3- or 1,4-diazabicyclo[3.2.2]nonanes to yield amides.