Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles

Latosińska, J.N.; Latosińska, Magdalena

doi:10.5772/29429

Cited by 6 publications

(5 citation statements)

References 177 publications

(186 reference statements)

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“…Throughout history of medicine the process of new drug discovery has been based on natural sources and drugs have been discovered by serendipity (sheer luck) or in a trial-and-error process. While until the mid-1980s new drugs were discovered mainly by serendipity, over the next decade, till mid-1990s, the knowledge of structure was the basis for research, then the starting point was to identify a target and a relationship between structure and function [122]. Nowadays a few major classes of drugs useful in cancer treatment have been defined: (1) General Chemotherapy Drugs (the alkylating agents, anti-neoplastics, anti-metabolites), (2) Steroids, (3) Bisphosphonates, (4) Hormone therapies and (5) Biological therapies/Immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Anticancer Drug Discovery — From Serendipity to Rational Design

Latosińska¹,

Latosińska²

2013

Drug Discovery

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the overall survival time increased significantly, especially in high-developed countries, but in fact the metastases, not the cancer itself, are the major cause of death. In 1971, only 50% of people diagnosed with the cancer went on to live at least five years, while nowadays, the fiveyear survival rate is 63% [2]. However if a cancer has spread the chances of survival are only scarcely better than in the 1970s. These numbers indicate that although the knowledge about cancer in the last two decades raised, even to a larger degree than in all preceding centuries, but the problem of cancer diseases persists and our knowledge is still insufficient to solve it. Despite the remarkable progress in cancer prevention, early detection, and treatment, made during the last few decades, the methods of cancer diagnosis and treatment are still not sufficiently specific and effective thus cancer still takes a heavy toll.Not so long ago in the beginning of 20 th century, neither carcinogens nor cellular targets were identified while the treatment was carried out exclusively by surgeries or natural products selected by trial and error. Modern cancer therapy based on the so-called holistic approachthe combined use of surgical methods, radiotherapy, chemotherapy, hormonal therapy and immunotherapy -is applied in the treatment of cancer at most stages. In fact this approach originated from the ancient Sumerian, Akkadian, Babylonian, Assyrian and Egyptian medicine, and was largely influenced by the Roman and Greek ideas concerning anatomy, physiology as well as the achievements of practical medicine and natural science. The chemotherapy, hormonal therapy, immunotherapy and radiotherapy as the methods of cancer treatment joined to the oldest surgical one only in the 20 th c. An important component of the combined therapy, but sometimes when cancer had already metastasised, the only available therapeutic method, is chemotherapy using natural or synthetic anticancer drugs and treated as curative, palliative, adjuvant or neoadjuvant. Over the centuries anticancer drugs evolved from natural products, discovered mainly from green plants and minerals to fully chemically synthesized chemotherapeutic agents. However, even today drugs of natural origin play an important role in the treatment of cancer as 14 of them were on the list of the top 35 drugs worldwide sales [4]. The process of anticancer drug discovery leading from natural products to chemotherapeutic agents, often illicitly limited only to cytostatic and antiproliferative, has evolved from serendipity to rational design based on advances in chemistry, physics and biology in a long and complicated process. Nowadays both cancer itself and anticancer drugs are investigated at the molecular level thus methods of drug discovery have changed diametrically. The dominant direction of contemporary aniticancer drug discovery is the search for the possibilities to influence the pathogenetic mechanisms specific of the tumour structures at the cellular and molecular levels, which require the kn...

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Section: Discussionmentioning

confidence: 99%

Anticancer Drug Discovery — From Serendipity to Rational Design

Latosińska¹,

Latosińska²

2013

Drug Discovery

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“…The change in conditions during the crystallization process (e.g., solvents, impurities, level of supersaturation, temperature, or stirring) allows the formation of different forms, which reveal differences in many physicochemical properties (such as solubility, dissolution rate, permeability, melting point, vapor pressure, crystal shape, compressibility, density, hardness, resistance to degradation, optical and electrical properties) but also chemical reactivity . Selection of the lowest energy polymorph, stable and easily controllable, is advisible according to the Q6A Guide of the International Council on Harmonization (ICH), as the polymorphism or phase transitions during the manufacture and storage may affect the bioavailability, the efficacy and safety, especially when dissolution is the absorption-limiting factor (Biopharmaceutics Classification System, classes II and IV) …”

Section: Introductionmentioning

confidence: 99%

Polymorphism and Thermal Stability of Natural Active Ingredients. 3,3′-Diindolylmethane (Chemopreventive and Chemotherapeutic) Studied by a Combined X-ray, ¹H–¹⁴N NMR-NQR, Differential Scanning Calorimetry, and Solid-State DFT/3D HS/QTAIM/RDS Computational Approach

Latosińska

Szafrański

et al. 2016

Crystal Growth & Design

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The compound 3,3'-diindolylmethane, DIM, is a major in vivo product of digestion of indole-3-carbinol, I3C, (phytochemical from Brassicaceae family plants) and main mediator of its chemopreventive and chemotherapeutic effects. In our previous paper (Europ. J. Pharm. Sci. 2015) we have reported the impact of structural differences between DIM and I3C on their biological activity. In this paper, the co-influence of two factors: polymorphism and temperature, on the topology, nature (coulombic/polarization/dispersion/repulsion) and strength of interaction pattern in DIM are in the area of our interest. Upon polymorph screening it has been found that DIM crystallizes in two polymorphic forms, form I (already known) and form II (newly obtained). DSC indicated slightly lower melting point for form I than for form II (436 versus 440 K) and the lack of phase transitions in both polymorphs. The crystal and molecular structures of both polymorphs have been determined as a function of temperature by single-crystal X-ray diffraction. The structure of polymorph I is monoclinic,molecule adopts a twisted (both 1H-indole rings are aligned along the same direction, but they are twisted by about 61.5 o ) and a half-chair (the molecule is bent, both 1H-indole rings make an angle of 68.9 o ) conformation, respectively, in forms I and II, which remain almost unaffected by temperature changes. Despite different relative orientations of both 1H-indole moieties in forms I and II, the differences in the interaction patterns revealed by Quantum Theory of Atoms in Molecules (QTAIM), Reduced Density Gradient (RDS), Hirshfeld surfaces (3D HS) and 2D Molecular Fingerprints (2D MF) are relatively small. The distribution of intermolecular interactions in the crystal of form II is by 5% less balanced than in that of form I. The Manhattan and Euclidean distances between the interactions do not exceed 3.76% and 2.21%, respectively, while Bhattacharaya coefficient does not exceed 0.35.Solid state PDB/DPN calculations have revealed that in solid the twisted conformation of the molecule is less stable by 118.7 kJ/mol than that of the half-hair one, but despite this, polymorph I is more stable due to a greater number of weak intermolecular interactions stabilizing the crystalline packing. (In the gas phase the half-hair conformation of the molecule is less stable by 0.788 kJ/mol than the twisted one, which may be attributed to the existence of many weak interactions and crystal packing effects in the solid state, which are absent in the gas phase.) The key interaction stabilizing the twisted versus chair conformation and determining crystalline packing in both polymorphs of DIM is the NH···π one. The factor responsible for the locked conformation of DIM in both forms is the electrostatic potential complementarity of the regions of N-H···π, linking neighboring molecules, which permits easy overcoming of any repulsive interactions that may force rotation of the molecule. The commercial sample of DIM was found to contain approximately 50% of form I and...

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“…The so-called “high-quality” counterfeit medicines pose a significant alert, since they may contain the correct composition but possibly differ in terms of excipients, ingredients, and manufacturing conditions. NQR has been proved to be an effective indicator of important structural information on the solid-state environment of the different crystal forms (polymorphs) due to the sensitivity from changes in the electron charge distribution surrounding the quadrupolar nucleus . A considerable line broadening is generally observed in NQR signals, originating from crystal defects or impurities existing in the material. ,, This aspect is directly correlated with the characterization of the physical and chemical properties, or similarly, the “stability” of the drug.…”

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confidence: 99%

“…A considerable line broadening is generally observed in NQR signals, originating from crystal defects or impurities existing in the material. ,, This aspect is directly correlated with the characterization of the physical and chemical properties, or similarly, the “stability” of the drug. Consequently, this can be influenced by the manufacturing conditions and processing (e.g., pressure) of the drug, the aging factor, and the environmental storage conditions such as the temperature and humidity. , Several studies have addressed the effect of those factors on the NQR resonance frequency and relaxation time constants. ,,,, In real applications, a database should contain statistically efficient “fingerprints” of the API and discrete formulations of each medicine. This includes different medicines, or medicines of the same formulation but produced by a different pharmaceutical company.…”

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Batch-Specific Discrimination Using Nuclear Quadrupole Resonance Spectroscopy

et al. 2015

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In this paper, we report on the identification of batches of analgesic paracetamol (acetaminophen) tablets using nitrogen-14 nuclear quadrupole resonance spectroscopy ((14)N NQR). The high sensitivity of NQR to the electron charge distribution surrounding the quadrupolar nucleus enables the unique characterization of the crystal structure of the material. Two hypothesis were tested on batches of the same brand: the within the same batch variability and the difference between batches that varied in terms of their batch number and expiry date. The multivariate analysis of variance (MANOVA) did not provide any within-batches variations, indicating the natural deviation of a medicine manufactured under the same conditions. Alternatively, the statistical analysis revealed a significant discrimination between the different batches of paracetamol tablets. Therefore, the NQR signal is an indicator of factors that influence the physical and chemical integrity of the material. Those factors might be the aging of the medicine, the manufacturing, or storage conditions. The results of this study illustrate the potential of NQR as promising technique in applications such as detection and authentication of counterfeit medicines.

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Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles

Cited by 6 publications

References 177 publications

Anticancer Drug Discovery — From Serendipity to Rational Design

Anticancer Drug Discovery — From Serendipity to Rational Design

Polymorphism and Thermal Stability of Natural Active Ingredients. 3,3′-Diindolylmethane (Chemopreventive and Chemotherapeutic) Studied by a Combined X-ray, ¹H–¹⁴N NMR-NQR, Differential Scanning Calorimetry, and Solid-State DFT/3D HS/QTAIM/RDS Computational Approach

Batch-Specific Discrimination Using Nuclear Quadrupole Resonance Spectroscopy

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Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles

Cited by 6 publications

References 177 publications

Anticancer Drug Discovery — From Serendipity to Rational Design

Anticancer Drug Discovery — From Serendipity to Rational Design

Polymorphism and Thermal Stability of Natural Active Ingredients. 3,3′-Diindolylmethane (Chemopreventive and Chemotherapeutic) Studied by a Combined X-ray, 1H–14N NMR-NQR, Differential Scanning Calorimetry, and Solid-State DFT/3D HS/QTAIM/RDS Computational Approach

Batch-Specific Discrimination Using Nuclear Quadrupole Resonance Spectroscopy

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Product

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Polymorphism and Thermal Stability of Natural Active Ingredients. 3,3′-Diindolylmethane (Chemopreventive and Chemotherapeutic) Studied by a Combined X-ray, ¹H–¹⁴N NMR-NQR, Differential Scanning Calorimetry, and Solid-State DFT/3D HS/QTAIM/RDS Computational Approach