Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5594_Библиотеки_им_академика_М_И_Перельмана

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Studies on physical parameters help to design potent biologically active struc-

To accelerate the process and follow environmentally benign methods, microwave-mediated reactions are performed. and many of these are considered anticancer agents. organocatalysis are followed to prepare diverse compounds with anticancer activities.

1.2 Monocyclic β-Lactams

As four-membered cyclic amides, monocyclic beta-lactams have a nucleus that has been modied in a number of ways which allows them to have a diverse chemical reactivity as well as target specicity. Unlike other beta-lactam families, this group of compounds consist of only the beta-lactam ring bound to a side chain, but their structures lack the thiazolidine, oxazolidine, and dihydrothiazine structures that characterize other beta-lactam families. There is an extensive history of their use based on their anti­bacterial properties, but they have recently found use in a variety of other areas as well. In most studies, monocyclic beta-lactams are identied as compounds that have antibacterial properties, while in some recent studies, monocyclic beta-lactams have been shown to have neuroprotective, anti-inammatory, anticancer, anticoagulant, and antihyperlipidemic properties.

It is known that monobactams are natural antibiotic compounds that are characterized by the presence of a monocyclic ring structure. In other words, the compounds are monocyclic, beta-lactam antibiot­ics that are produced by bacteria. It should be noted that the beta-lactam ring is not fused to another ring, contrary to what is found in most other beta-lactams.74 A group of investigators from the Squibb Institute of Medical Research and Imeda et al. discovered these compounds in 1981 as part of inde­pendent teams of investigators. There are many natural soil inhabitants that produce these monocy­clic beta-lactams, which include Chromobacterium, Agrobacterium, Gluconobacter, Flexibacter, and

There is no cross-reactivity between monobactam antibiotics and penicillin, but there has been some cross-reactivity with cephalosporin antibiotics, especially ceftazidime, which has an identical side chain to aztreonam, although it is untested. The risk of seizures being triggered by monobactams is slightly lower than the risk of seizures being triggered by penicillin in patients with a history of seizures.

crystals, exhibits moderate antibacterial activity in vitro against a wide range of Gram-negative bacteria, including Proteus and Pseudomonas. The toxicity of this compound in laboratory animals was very low. In regard to the nocardicins (nocardicins A to G), nocardicin A (Fig u re 1.1) has been shown to be the most active. Biologically, and from a stereochemical point of view, it resembles penicillin and cephalo­sporins in many ways.

The structural differences among nocardicins can be attributed to the homoserine side chain in nocar­dicins A, B, C, and D, whereas that side chain is absent in nocardicins E, F, and G. There is also the presence of an oxime group at the C3 position of the monobactam ring in nocardicins A, B, E, and F. Nocardicins were later isolated from M. caesia, N. atra, and A. mirum.

There is no doubt that serine is the precursor of the beta-lactam ring in most of the monocyclic beta­lactams that have been studied. In unicellular bacterial monobactams, the acyl group is derived from D-glutamyl-D (or L)-alanine. Nocardicins have been the subject of the majority of biosynthetic stud­ies in the past. Incorporating the precursors into nocardicin A reveals that the compound is formed from L-serine, L-homoserine, and L-tyrosine, which are metabolized to the direct precursor, a non­proteinogenic amino acid called L-p-hydroxyphenylglycine (L-pHPG). The nocardicins G and E have been found to be precursors to the nocardicins C and A, respectively. In nocardicins E, F, and G, an S-adenosylmethionine-dependent enzyme catalyzes the addition of the homoseryl side chain to a pheno­lic group. It has been found that this enzyme (Mr 33.22 kDa) shares some homology with methyl trans­ferases in its structure. In order to purify it to homogeneity, it was subjected to afnity chromatography to S-adenosylhomocysteine and nocardicin A-agarose as separate steps. In order to clone the nat gene from the genome of N. uniformis, internal peptides were used.

Furthermore, the cluster also contains genes that encode tailoring enzymes that play an important role in the modication of nocardicins. The nocL gene encodes a cytochrome P450 enzyme that is catalyzed to form the syn-congured oxime moiety of nocardicin A. When nocL is disrupted, there is a lack of production of metabolites containing the oxime moiety; however, when the null mutant is transformed with nocL, this production is restored.

To obtain a pale brown precipitate, the active solution was adjusted to a pH of 2.5. After the precipitate was collected, it was suspended in water, and the suspension was then adjusted to a pH of 7.5 with 4 N aqueous sodium hydroxide. An anion-exchange resin column was used to pass the solution through as it was being processed. Aqueous ammonia solution was used to elute the absorbate from the column after it had been washed with water. A crystalline powder was obtained from the eluate after 4 N hydrochloric acid was added to adjust the pH to 2.5. The crude crystals were then recrystallized from acidic water after having been treated with charcoal in order to yield colorless ne needles. A yield of 3.6 grams of nocardicin A was obtained from 20 liters of a fermentation broth containing 500 micrograms per milliliter.

The ultraviolet absorption spectrum of nocardicin A in 1/15 m phosphate buffer solution (pH 8.0) and in 0.1 N aqueous sodium hydroxide solution was reported. There is a shoulder at 220 nm and a maximum at 272 nm in the presence of phosphate buffer, as well as maxima at 244 nm and 283 nm in the presence of alkaline solutions.

The spectrum of its infrared absorption, measured in nujol, showed peaks at the following frequencies: 3450, 3250, 3200, 2700–2500, 1725, 1655, 1605, 1590, 1510, 1395, 1260, 1240, 1220, 1175, 1045, 930, 840, 810, and 720 cm-1.

Among the various monobactam antibiotics available on the market, aztreonam (AZM) (Figure 1.2) is one of the most commonly used. The basic mononucleus of AZM contains a sulfonic acid group on the number one nitrogen, which is responsible for activating the lactam ring in the compound. It is believed that the aminothiazolyl oxime side chain at position 3 is responsible for the activity against Gram­negative bacteria. P. aeruginosa is more susceptible to the presence of the carboxyl group in the side chain. It is important to note, however, that the presence of this group has a diminished effect on the activity against Gram-positive organisms. In order for beta-lactamases to be stable, they have an alpha­methyl group at position 4.

There are several different brands of AZM available in the market, including Azactam, which is an antibiotic used to treat infections caused by Gram-negative bacteria such as P. aeruginosa. This can include bone infections, endometritis, intra-abdominal infections, pneumonia, urinary tract infections, and sepsis to name a few. There are several ways in which the medication can be administered: intrave­nously, intramuscularly, or by inhalation.

There have been reports of injection-site reactions, rash, and rarely toxic epidermal necrolysis associ­ated with this medication. A common side effect of the drug on the gastrointestinal tract is diarrhea, nau­sea, and vomiting. Drugs may cause eosinophilia as a side effect. There are many similarities between the action of AZM and that of penicillin. By blocking the cross-linking of peptidoglycan chains, it inhibits the synthesis of the bacterial cell wall. The penicillin-binding protein-3 has a very high afn­ity to it, while penicillin-binding protein-1a has a mild afnity to it. AZM binds very poorly to PBPs in Gram-positive bacteria and anaerobic bacteria, so it is largely ineffective against Gram-positive bacteria and anaerobic bacteria. Despite the fact that AZM is a bactericidal agent, it is less effective than some of the cephalosporins.

Source: Adapted with permission from Mani et al. (2023).