Synthesis and diverse biological activity profile of triethylammonium isatin-3-hydrazones

A series of biorelevant triethylammonium isatin hydrazones containing various substituents in the aromatic fragment have been synthesized. Their structure and composition were confirmed by NMR- and IR-spectroscopies, mass-spectrometry and elemental analysis. It was found that some representatives show activity against Staphylococcus aureus and Bacillus cereus higher or at the level of norfloxacin, including methicillin-resistant Staphylococcus aureus strains. The study also showed low hemo- and cytotoxicity (Chang Liver) and high antiaggregatory and anticoagulant activity of these compounds. The high potential of new ammonium isatin-3-acylhydrazones in the search for antimicrobial activity against phytopathogens of bacterial and fungal nature has been shown for the first time.

Transformations of 3,7-interphenylene 11-deoxyprostanoid formyl precursors in the acidic medium

It has been shown that the formyl precursors of 3,7-interphenylene 11-deoxyprostanoids, formed during acidic hydrolysis of the corresponding acetals, can undergo isomerization (disproportionation) in the acidic medium to give 2-(arylalkyl)-3-(hydroxymethyl)cyclopent-2-ene-1-ones – the synthons for prostanoids and phytoprostanes of the series B. Acetal precursors of 3,7-interphenylene 11-deoxyprostaglandin analogues with electron-donating alkoxy substituent in position 3′ of the aromatic fragment in the α-chain under similar conditions hydrolyze with the formation of formyl derivatives that spontaneously cyclize to produce 2,3,4,9-tetrahydro-1H-cyclopenta[b]naphthalene-1-ones.

The Total Synthesis of Aigialomycin D and Analogues

<p>In 2002 a new family of 14-membered resorcylic macrolides, the aigialomycins, were isolated from the mangrove fungus Aigialus parvus BCC 5311. Subsequent biological testing of these new natural products found aigialomycin D (Am D) to be the most biologically active member of the family, exhibiting moderate activity against malaria (Plasmodium falciparum K1, IC50 19.7 Mu) and modest cytotoxicity towards certain cancer cells (KB cells: IC50 9.0 Mu and BC-1 cells: 53.8 Mu). More recently, Am D has been shown to inhibit the kinases CDK1/5 and GSK at low Mu concentrations. At the onset of this research project, with only one total synthesis of Am D reported in the literature, there remained a need for an efficient synthesis of Am D that would be amenable to the synthesis of a range of analogues. This thesis reports two synthetic approaches to Am D that differ primarily in the chemistry utilised to install the (E)-olefins at C1'-C2' and C7'-C8': a Horner-Wadsworth-Emmons (HWE) strategy and a Ramberg-Backlund (RB) strategy. The Ramberg-Backlund strategy ultimately proved to be successful, providing Am D in 16 steps with 9% overall yield. A retrosynthetic analysis of Am D disconnects the molecule into three major fragments: an aromatic fragment, a C2'-C7' carbohydrate-derived fragment and a C8'-C11' alcohol fragment. The synthesis of the three fragments for each strategy is described and the attempts made to couple the fragments together, first with HWE methodology and then successfully with ring-closing metathesis (RCM) and RB reactions, are discussed. The synthesis of several Am D analogues and their preliminary biological testing is also described.</p>

The Total Synthesis of Aigialomycin D and Analogues

<p>In 2002 a new family of 14-membered resorcylic macrolides, the aigialomycins, were isolated from the mangrove fungus Aigialus parvus BCC 5311. Subsequent biological testing of these new natural products found aigialomycin D (Am D) to be the most biologically active member of the family, exhibiting moderate activity against malaria (Plasmodium falciparum K1, IC50 19.7 Mu) and modest cytotoxicity towards certain cancer cells (KB cells: IC50 9.0 Mu and BC-1 cells: 53.8 Mu). More recently, Am D has been shown to inhibit the kinases CDK1/5 and GSK at low Mu concentrations. At the onset of this research project, with only one total synthesis of Am D reported in the literature, there remained a need for an efficient synthesis of Am D that would be amenable to the synthesis of a range of analogues. This thesis reports two synthetic approaches to Am D that differ primarily in the chemistry utilised to install the (E)-olefins at C1'-C2' and C7'-C8': a Horner-Wadsworth-Emmons (HWE) strategy and a Ramberg-Backlund (RB) strategy. The Ramberg-Backlund strategy ultimately proved to be successful, providing Am D in 16 steps with 9% overall yield. A retrosynthetic analysis of Am D disconnects the molecule into three major fragments: an aromatic fragment, a C2'-C7' carbohydrate-derived fragment and a C8'-C11' alcohol fragment. The synthesis of the three fragments for each strategy is described and the attempts made to couple the fragments together, first with HWE methodology and then successfully with ring-closing metathesis (RCM) and RB reactions, are discussed. The synthesis of several Am D analogues and their preliminary biological testing is also described.</p>

Estrogens and antiestrogens. Modern synthetic approaches to directed modification of estra-1,3,5(10)-triene steroids: goals, reactions, and methods

The monograph summarizes the information over the past 20 years on the currently widely used and promising methods for the synthesis of estra-1,3,5(10)-triene derivatives by modifying natural estrogens - estrone and estradiol. The main practical goals of modifying this class of steroids and achievements in the chemistry of steroidal antiestrogens, which are promising drugs for hormonal therapy, are considered. Special attention is paid to the stereochemical features of the reactions and the specific problems of modification of the steroid nucleus of estratrienes associated with the presence of an aromatic fragment in their structure. In addition, the data on the reactivity and stereochemical aspects of the transformations of 13-epiestratriene steroids were summarized. The monograph is intended for a wide range of specialists in the field of organic synthesis, organic, bioorganic, and medicinal chemistry.

EPOXYACRYLATE-BASED PHOTOPOLYMERIZABLE COMPOSITIONS FOR THERMOOXIDATIVE RESISTANT MATERIALS

The characteristics of thermooxidative degradation of the samples of cured epoxy acrylates based on epoxy resins ED-20 and UP-637, as well as their compositions with oligoether acrylate TGM-3, were investigated by the method of simultaneous thermal analysis. It has been found that the photopolymers have a sufficiently high resistance to thermal oxidation, the start temperature of active thermal destruction exceeds 325 ° C. Differences in the chemical structure of the aromatic fragment determine the features of thermal resistance. The addition of an active diluent to the composition is capable to reduce the internal stresses of the polymer structure and to promote a shift in the onset of thermal oxidation to higher temperatures.

Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening

Despite extensive and intensive research efforts in recent decades, there is still no effective treatment for neurodegenerative diseases. On this background, the use of drugs inhibiting the enzyme acetylcholinesterase (AChE) remains an eternal evergreen in the symptomatic treatment of mild to moderate cognitive impairments. Even more, the cholinergic hypothesis, somewhat forgotten in recent years due to the shift in focus on amyloid cascade, is back to life, and the search for new, more effective AChE inhibitors continues. We generated a fragment-based library containing aromatic moieties and linkers originating from a set of novel AChE inhibitors. We used this library to design 1220 galantamine (GAL) derivatives following the model GAL (binding core) - linker (L) - aromatic fragment (Ar). The newly designed compounds were screened virtually for blood–brain barrier (BBB) permeability and binding to AChE. Among the top 10 best-scored compounds, a representative lead molecule was selected and tested for anti-AChE activity and neurotoxicity. It was found that the selected compound was a powerful non-toxic AChE inhibitor, 68 times more active than GAL, and could serve as a lead molecule for further optimization and development.

Antiproliferative, Antimicrobial and Antiviral Activity of β-Aryl-δ-iodo-γ-lactones, Their Effect on Cellular Oxidative Stress Markers and Biological Membranes

The aim of this work was the examination of biological activity of three selected racemic cis-β-aryl-δ-iodo-γ-lactones. Tested iodolactones differed in the structure of the aromatic fragment of molecule, bearing isopropyl (1), methyl (2), or no substituent (3) on the para position of the benzene ring. A broad spectrum of biological activity as antimicrobial, antiviral, antitumor, cytotoxic, antioxidant, and hemolytic activity was examined. All iodolactones showed bactericidal activity against Proteus mirabilis, and lactones 1,2 were active against Bacillus cereus. The highest cytotoxic activity towards HeLa and MCF7 cancer cell lines and NHDF normal cell line was found for lactone 1. All assessed lactones significantly disrupted antioxidative/oxidative balance of the NHDF, and the most harmful effect was determined by lactone 1. Contrary to lactone 1, lactones 2 and 3 did not induce the hemolysis of erythrocytes after 48 h of incubation. The differences in activity of iodolactones 1–3 in biological tests may be explained by their different impact on physicochemical properties of membrane as the packing order in the hydrophilic area and fluidity of hydrocarbon chains. This was dependent on the presence and type of alkyl substituent. The highest effect on the membrane organization was observed for lactone 1 due to the presence of bulky isopropyl group on the benzene ring.