Category: Chemistry

Highly Efficient Photolabile Protecting Groups with Intramolecular Energy Transfer

No Comments

The light sensitivity of photolabile protecting groups of the nitrophenylpropoxycarbonyl (NPPOC) type was enhanced by up to a factor of 25. This was achieved by covalently linking the protecting group to a sensitizer with a much better absorptivity and the ability to transfer its electronic excitation to the protecting group (see scheme).


Synthesis and Pharmacological Effects of Diosgenin–Betulinic Acid Conjugates

The target diosgenin–betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate  buy Pregabalin Lyrica uk v 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate  can you buy gabapentin online reddit 8 showing no cytotoxicity, and diosgenin ( 1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition,  5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.

Diosgenin, (3β,25R)-spirost-5-en-3-ol, is a steroid sapogenin part of the saponin dioscin found in the tubers of Dioscorea zingiberensis C. H. Wright or Trigonella foenum-graecum L. and in numbers of legumes. Diosgenin is a widely used precursor in the synthesis of sexual hormones, peroral contraceptives and other steroids in the pharmaceutical industry. It is an adaptogen, displaying non-steroidogenic activity along with other beneficial effects. Diosgenin is unable to bind metal ions, and therefore, the change made from more traditional cholesterol/cholesterylamine system to diosgenin could influence the overall conformation of the bivalent structures, modifying the metal ions chelating properties. Saponins are always species formed from an aglycone and several monosaccharide units, the presence of which increases the solubility of saponins in natural aqueous media. Diosgenin is not metabolized in the human body, and it is considered to represent a safe natural drug. It has also been investigated for treating hyperglycemia, hypercholesterolemia, hypertriacylglycerolemia, and Alzheimer’s disease.
Betulinic acid, 3β-hydroxylup-20(29)-en-28-oic acid, is a pharmacologically perspective triterpenoid plant product with a broad spectrum of effects, e.g., antitumor, anti-HIV, cytostatic, and anti-inflammatory. It can be obtained from the bark of Betula pendula Roth, widely distributed in Europe, and from a number of subtropical and tropical plants. (Molecules. 2020 Aug; 25(15): 3546.)

Mitocanic Di- and Triterpenoid Rhodamine B Conjugates

The combination of the “correct” triterpenoid, the “correct” spacer and rhodamine B (RhoB) seems to be decisive for the ability of the conjugate to accumulate in mitochondria. So far, several triterpenoid rhodamine B conjugates have been prepared and screened for their cytotoxic activity. To obtain cytotoxic compounds with EC50 values in a low nano-molar range combined with good tumor/non-tumor selectivity, the Rho B unit has to be attached via an amine spacer to the terpenoid skeleton. To avoid spirolactamization, secondary amines have to be used. First results indicate that a homopiperazinyl spacer is superior to a piperazinyl spacer. Hybrids derived from maslinic acid or tormentic acid are superior to those from oleanolic, ursolic, glycyrrhetinic or euscaphic acid. Thus, a tormentic acid-derived RhoB conjugate 32, holding a homopiperazinyl spacer can be regarded, at present, as the most promising candidate for further biological studies.

An external file that holds a picture, illustration, etc.
Object name is molecules-25-05443-g001.jpg

Mitochondrial membranes of malignant cells hold an increased membrane potential compared to non–malignant cells. This effect fosters the accumulation of cationic molecules, hence inducing high selectivity for mitocans holding a (more or less) lipophilic cation such as a rhodamine scaffold. The same effect applies for triphenylphosphonium cations and to a small extent for quaternary ammonium ions, zwitterionic N-oxides and triterpenes substituted with BODIPYs or a safirinium moiety [67].
To date, hybrid molecules have been prepared from oleanolic acid (OA, Figure 2), ursolic acid (UA), glycyrrhetinic acid (GA), betulinic acid (BA), maslinic acid (MA), augustic acid (AU), 11-keto-β-boswellic acid (KBA), asiatic acid (AA), tormentic acid (TA) and euscaphic acid (EA).
OA-derived RhoB conjugates appear to be superior to analog UA-derived compounds in the majority of cases with respect to their cytotoxicity. Although AKBA-derived derivatives have good cytotoxicity properties, they were found to be less cytotoxic compared to other triterpene carboxylic acid derivatives, but they often showed better tumor cell/non-tumor cell selectivity. So far, the best cytotoxicity properties have been found for MA-, EA- and TA-derived derivatives. These allowed the transition to compounds of nano-molar activity, while many other triterpene carboxylic acid derivatives were cytotoxic only on a micro-molar concentration range. MA- derived derivatives seem to be approximately equivalent to EA-derived compounds. They are currently only surpassed in many tumor cell lines only by the analogous derivatives from TA. From results available so far, it can be concluded that compounds holding a homopiperazinyl spacer are superior to those with a piperazinyl spacer. This underlines the importance of the spacer for obtaining good cytotoxicity properties. (Molecules. 2020 Nov; 25(22): 5443.)