scholarly journals Use of Organosilicon Compounds towards the Rational Design of Antiparasitic and Antiviral Drugs

1995 ◽  
Vol 2 (3) ◽  
pp. 143-151 ◽  
Author(s):  
Gérard Déléris
Keyword(s):  
Reverse Transcriptase ◽  
Antisense Oligonucleotides ◽  
Rational Design ◽  
Chemical Properties ◽  
Therapeutic Agents ◽  
Main Group ◽  
Biologically Active ◽  
Hiv Reverse Transcriptase ◽  
Antiparasitic Drugs ◽  
High Level

One of the major problems met for the conception of antiviral or antiparasitic drugs is to reach a high level of selectivity towards the pathogenic agent versus the host. We shall describe two synthetic approaches where main group organometallics have been used towards this goal. A series of nucleoside sila-analogues was synthesized as potential therapeutic agents designed to inhibit HIV Reverse Transcriptase. In a second approach novel organosilicon derivatives have been synthesized as mimics of antisense oligonucleotides.Infectious agents, namely viruses or parasites, more or less use cellular machinery. Therefore therapeutic agents must interfere with biochemical mechanisms or possess high affinity towards specific molecular cellular components, to reach selectivity.We thought that main group organometallics could show many advantages for designing biologically active molecules in this field. They allow a high synthetic flexibility for the modulations of physico-chemical properties and they show a mechanistic behaviour which may be close to the one of several heteroelements present in living organisms such as sulfur or phosphorus.We tried to use this approach towards two directions involving the synthesis of organosilicon derivatives i.e:-the synthesis of organosilicon derivatives as inhibitors of HIV Reverse Transcriptase,-the synthesis of organosilicon precursors of modified antisense oligonucleotides.

Synthesis of azabicycloalkanone amino acid and azapeptide mimics and their application as modulators of the prostaglandin F2α receptor for delaying preterm birth

2014 ◽  
Vol 92 (11) ◽  
pp. 1031-1040 ◽  
Author(s):  
Carine B. Bourguet ◽  
Audrey Claing ◽  
Stéphane A. Laporte ◽  
Terence E. Hébert ◽  
Sylvain Chemtob ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Amino Acid ◽  
Rational Design ◽  
Prostaglandin F2α ◽  
Receptor Activation ◽  
Therapeutic Agents ◽  
Biologically Active ◽  
Mortality And Morbidity ◽  
Amino Acid Peptide ◽  
Uterine Contractions

Premature birth (<37 weeks gestation) is the major cause of perinatal mortality and morbidity and has been steadily increasing worldwide. Towards the rational design of more effective therapeutic agents for inhibiting uterine contractions and prolonging gestation (a so-called tocolytic drug), our team has targeted the prostaglandin F2α receptor (FP) employing a peptidomimetic approach designed to provide modulators of this novel target. We identified first a lead peptide (PDC113) (1) based on the sequence of the second extracellular loop of FP on the basis that the loop itself might modulate receptor activation. Systematic study of the structure−activity relationships of 1 generated hypotheses concerning the conformation and side-chains responsible for activity that led to the synthesis of PDC113.31 (2), a potent all d-amino acid peptide, which has successfully completed Phase 1b clinical trials. Employing indolizidinone amino acids, peptide mimics were developed that served to probe the mechanism of FP modulation. For example, PDC113.824 (9) was shown to allosterically regulate FP activity contingent on the presence of prostaglandin F2α by a mechanism implicating biased signalling. Although attempts to understand the turn geometry responsible for the activity of 9 by replacement of its indolizidin-2-one moiety with other azabicycloalkanones failed to produce biologically active analogs, employment of aza-aminoacyl-proline analogs resulted in a series of FP modulators exhibiting distinct effects on different G protein-mediated signalling pathways. Our program has thus contributed novel probes for understanding the chemical biology of FP as well as new therapeutic agents with promise for inhibiting uterine contractions and preventing preterm birth.

scholarly journals Positional Effect of π-extension in Triple Helicenes

2021 ◽  
Author(s):  
Alex van der Ham ◽  
Thomas Hansen ◽  
Hermen S. Overkleeft ◽  
Trevor A. Hamlin ◽  
Dmitri V. Filippov ◽  
...  
Keyword(s):  
Optical Properties ◽  
Rational Design ◽  
Marked Effect ◽  
Chemical Properties ◽  
Spectroscopic Properties ◽  
Positional Effect ◽  
Physico Chemical ◽  
Optical Applications ◽  
High Level ◽  
Vt Nmr

The targeted application of multiple helicenes in photo-optical applications requires their rational design. Toward this goal, we report on the synthesis of pyrene-based triple helicene 1 and investigate the positional effect of extension of the π-conjugated system on the photo-chemical and chiro-optical properties of triple helicenes. The conformational and aggregatory behavior of 1 were studied both experimentally using VT NMR spectroscopy and computationally using high-level DFT computations. Although π-extension was observed to have a marked effect on the spectroscopic properties of triple helicenes, comparison with other known π-extended helicenes reveals that the position at which π-extension is introduced is only of nominal importance. Our results thus suggest that the presence of a particular helicene motif is dominant in dictating the physico-chemical properties of triple helicenes.

Biologically active polymeric sequestrants: Design, synthesis, and therapeutic applications

2007 ◽  
Vol 79 (9) ◽  
pp. 1521-1530 ◽  
Author(s):  
Pradeep K. Dhal ◽  
Chad C. Huval ◽  
S. Randall Holmes-Farley
Keyword(s):  
Rational Design ◽  
Biological Activities ◽  
Functional Polymers ◽  
Therapeutic Agents ◽  
The Body ◽  
Biologically Active ◽  
Gi Tract ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Polymeric Drugs

In recent years, functional polymers exhibiting inherently biological activities have been receiving increasing attention as polymer-based human therapeutic agents. These polymeric drugs exhibit unique pharmaceutical properties that are fundamentally different from their traditional small-molecule counterparts. However, unlike polymeric drug delivery systems, examples of polymers possessing intrinsically therapeutic properties are relatively scarce. By virtue of their high-molecular-weight characteristics, these polymeric drugs can be confined to the gastrointestinal (GI) tract, where they can selectively recognize, bind, and remove target disease-causing substances from the body. Being confined to the GI tract and non-biodegradable, these polymeric drugs are free from toxic effects that are associated with traditional systemic drugs. This report highlights recent developments in the rational design and synthesis of appropriate functional polymers that have resulted in a number of promising polymer-based therapeutic agents, including some marketed products.

scholarly journals Positional Effect of π-extension in Triple Helicenes

2021 ◽  
Author(s):  
Alex van der Ham ◽  
Hermen S. Overkleeft ◽  
Dmitri V. Filippov ◽  
Grégory F. Schneider
Keyword(s):  
Optical Properties ◽  
Nmr Spectroscopy ◽  
Rational Design ◽  
Marked Effect ◽  
Chemical Properties ◽  
Positional Effect ◽  
Physico Chemical ◽  
Optical Applications ◽  
High Level ◽  
Vt Nmr

Application of multiple helicenes in photo‐optical applications requires their rational design. We therefore here report on the synthesis of pyrene‐based triple helicene 1, to study the positional effect of extension of the π‐conjugated system on the photo‐chemical and chiro‐optical properties of triple helicenes. The conformational and aggregatory behavior of 1 were studied both experimentally using VT NMR spectroscopy and computationally using high‐level DFT computations. Although π‐extension was observed to have a marked effect on the spectroscopy properties of triple helicenes, comparison with other known π‐extended helicenes reveals that the position at which π‐extension is introduced is only of nominal importance. Our results thus suggest that the presence of a particular helicene motive is dominant in dictating the physico‐chemical properties of triple helicenes.

scholarly journals K70Q Adds High-Level Tenofovir Resistance to “Q151M Complex” HIV Reverse Transcriptase through the Enhanced Discrimination Mechanism

PLoS ONE ◽  
2011 ◽  
Vol 6 (1) ◽  
pp. e16242 ◽  
Author(s):  
Atsuko Hachiya ◽  
Eiichi N. Kodama ◽  
Matthew M. Schuckmann ◽  
Karen A. Kirby ◽  
Eleftherios Michailidis ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Hiv Reverse Transcriptase ◽  
High Level

In the Quest for a Stable Triplet State in Small Polyaromatic Hydrocarbons : An In-Silico Tool for Rational Design and Prediction

2019 ◽  
Author(s):  
Madhumita Rano ◽  
Sumanta K Ghosh ◽  
Debashree Ghosh
Keyword(s):  
Triplet State ◽  
Small Molecules ◽  
In Silico ◽  
Qualitative Agreement ◽  
Rational Design ◽  
Polyaromatic Hydrocarbons ◽  
Spin Hamiltonian ◽  
Spin Frustration ◽  
Computationally Efficient ◽  
High Level

<div>Combining the roles of spin frustration and geometry of odd and even numbered rings in polyaromatic hydrocarbons (PAHs), we design small molecules that show exceedingly small singlet-triplet gaps and stable triplet ground states. Furthermore, a computationally efficient protocol with a model spin Hamiltonian is shown to be capable of qualitative agreement with respect to high level multireference calculations and therefore, can be used for fast molecular discovery and screening.</div>

Antioxidant status of blood in patients with vibration disease

2019 ◽  
pp. 978-982 ◽  
Author(s):  
N. N. Malyutina ◽  
A. F. Bolotova ◽  
R. B. Eremeev ◽  
A. Zh. Gilmanov ◽  
D. Yu. Sosnin
Keyword(s):  
Antioxidant Activity ◽  
Blood Serum ◽  
Antioxidant Status ◽  
Total Antioxidant Status ◽  
Main Group ◽  
Biologically Active ◽  
Antioxidant Systems ◽  
Control Group ◽  
Vibration Disease ◽  
Total Antioxidant

Introduction. The overwhelming number of publications contains only data on the content of individual antioxidants, but not on the overall antioxidant activity of the blood in patients with vibration disease.The aim of the study was to determine the total antioxidant activity of blood serum in patients with vibration disease.Materials and methods. Th e main group consisted of 30 people diagnosed with “Vibration disease” of 1 degree (n=21) and 2 degrees (n=9). Th e control group consisted of 30 clinically healthy men, comparable in age with the main group (p=0.66). Th e total activity of antioxidant systems of blood plasma was evaluated photometrically using the test system “Total antioxidant status-Novo” (“Vector-best”, Russia).Results. The indicator of the total antioxidant status (TAS) was 1,038±0.232 mmol/l in the examined main group, against 1,456±0.225 mmol/l in the examined control group (p<0.000001). Th e coefficient of variation (CV) in patients with vibration disease was 22.35%, 1.45 times higher than in the control group (15.45%). In the main group there was a positive correlation between age and TAS (R=0.525), in the control group there was no such relationship (R=0.095). Th e degree of decrease depended on the severity of vibration disease.Conclusions. 1. The development of vibration disease is accompanied by a decrease in the antioxidant status of blood serum. 2. Th e degree of decrease in the antioxidant status of blood serum correlates with the severity of vibration disease. 3. Reduction of TAS can serve as a pathogenetic justification of the need to include drugs and/or biologically active additives with antioxidant activity in therapy

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