Containing biomolecules, reaction products

H. Reaction Products of Pt-Amine Compounds and Sulfur-Containing Biomolecules... 

A second mechanism of inactivation might be the reaction of sulfur-containing biomolecules with the cis-Pt-DNA monoadducts (product 1 in Fig. 4), which prevents those from rearranging to toxic bifunctional adducts. Supportive for such a mechanism is the observation that GSH can be cross-linked to DNA by cis-Pt (41,41a) and [Pt(en)Cl2] (74), and that cysteine can be cross-linked to d-Guo by cis-Pt (77). Furthermore, cis-Pt-DNA monoadducts can be experimentally quenched with thiourea, which reduces drug toxicity (82, 83). trans-Pt also yields monofunctional adducts after reaction with DNA, and these rearrange somewhat slower than does cis-Pt into bifunctional adducts (41,84), clearly for sterical reasons. The relatively long-living monofunctional adducts react efficiently with GSH and proteins (41 a, 84-86). 

To investigate the kinetics in more detail, the reaction rates of a simple pair of model compounds, [Pt(dien)X] [(X = Cl-, H2O) with GSH, GS-Me and 5 -GMP have been investigated and compared (164). The reaction products with GSH and GS-Me are shown in Fig. 10 an overview of the reactions between [Pt(dien)Cl] and GSH is presented in Scheme 2. These products are the first well-identified complexes between S-containing biomolecules and platinum amine compounds (130) and therefore are ideally suited as model compounds for kinetic studies. The results of the reactions are summarized in Table IV. In agreement with the above-mentioned hypothesis, the chloride hydrolysis is the rate-determining step in the reaction of [Pt(dien)Cl]+ with 5-GMP,... 

The high affinity of many platinum compounds for sulfur and the availability of many sulfur-containing biomolecules have raised the question whether Pt-sulfur biomolecule interactions could serve as a drug reservoir for platination at DNA, necessary for the antitumor activity of cis-Pt. Two reaction paths are possible, i.e., spontaneous release of plantinum from the sulfur, or nucleophilic displacement of platinum from sulfur by guanine (N7), for example. At the moment, there is no real evidence for the existence of such reactivation mechanisms. In fact, it has been reported that Pt-protein interactions in the plasma (albumin) are not reversible under normal conditions (161, 165). Further, a mixture of cis-Pt-methionine products does not show antitumor properties (166), indicating no induced platination of DNA. More research is required to investigate the existence of a reactivation mechanism. However, it is predicted that if such a reactivation phenomenon is operational, the most likely candidate is the labile Pt-methionine bond, as has been shown by its rapid reaction with Naddtc, STS, and thiourea (vide supra) (131). 

The question of the stability of the biomolecules is a vital one. Could they really have survived the tremendous energies which would have been set free (in the form of shock waves and/or heat) on the impact of a meteorite Blank et al. (2000) developed a special technique to try and answer this question. They used an 80-mm cannon to produce the shock waves the shocked solution contained the two amino acids lysine and norvaline, which had been found in the Murchison meteorite. Small amounts of the amino acids survived the bombardment , lysine seeming to be a little more robust. In other experiments, the amino acids aminobutyric acid, proline and phenylalanine were subjected to shock waves the first of the three was most stable, the last the most reactive. The products included amino acid dimers as well as cyclic diketopiperazine. The kinetic behaviour of the amino acids differs pressure seems to have a greater effect on the reaction pathway than temperature. As had been recognized earlier, the effect of pressure would have slowed down certain decomposition reactions, such as pyrolysis and decarboxylation (Blank et al., 2001). 

An important exception to this regularity is the cyclization of aromatic alkoxides containing aromatic radical moieties. In these cases, C-0 bond formation is not observed, but C-C bond formation is achieved instead. As Galli and Gentili (1998) pointed out, this is primarily due to the unfavorable thermodynamic driving force for C-0 bond formation compared to C-C bond formation. Thus, the photostimulated reaction depicted in Scheme 7.39 results in the formation of a six-membered carbocycle rather than an octa-membered oxa-heterocycle. The carbocycle is formed in 75% yield (Barolo et al. 2006). This product is a precursor to the thalicmidine biomolecule of the alkaloid group. 

The production of humic substances by microorganisms is an extracellular process, because the enzymes are secreted into the external solution that contains the phenolic compounds derived from lignin and tannic acid degradation and microbial and plant metabolites. These phenolic compounds can then be enzymatically oxidized to quinones, which can undergo further polymerization or polycondensation reactions with other biomolecules (e.g., amino acids) to form humic polymers (Stevenson, 1994 Bollag et al., 1998 Burton, 2003). 

Microencapsulation has also been used medically for the encapsulation of live cells and vaccines. Biocompatibility can be improved by the encapsulation of artificial cells and biomolecules such as peptides, proteins, and hormones, which can prevent unwanted immunological reactions that would lead to inactivation or rejection. Microspheres are used for isolating materials until their activity is needed. The biotechnology industry employs microspheres to contain organisms and their recombinant products to aid in the isolation of these products. ... 

The removal of HzO from biomolecules containing alcohol functional groups is a commonly encountered reaction. A prominent example of this reaction is the dehydration of 2-phosphoglycerate, an important step in carbohydrate metabolism (Figure 1.17). Other products of elimination reactions include ammonia (NH3), amines (RNH2), and alcohols (ROH). 

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