New Classification Framework of Tetracyclines And

Cornell University Library Arxiv.org/quantitative-biology/biomolecules New Classification Framework and Structure-Activity- Relationship (SAR) of Tetracycline-Structure-Based Drugs Domenico Fuoco, Pharm.D., Ph.D BioTech Consultant; Member of Italian National Order of Chemists and Italian Chemical Society in Rome, Italy By studying the literature about Tetracyclines (TCs), it becomes clearly evident that TCs are very dynamic molecules. In some cases, their structure-activity-relationship (SAR) are known, especially against bacteria, while against other targets, they are virtually unknown. In other diverse yields of research, such as neurology, oncology and virology the utility and activity of the tetracyclines are being discovered and are also emerging as new technological fronts. The first aim of this paper is classify the compounds already used in therapy and prepare the schematic structure in which include the next generation of TCs. The aim of this work is introduce a new framework for the classification of old and new TCs, using a medicinal chemistry approach to the structure of that drugs. A fully documented Structure-Activity-Relationship (SAR) is presented with the analysis data of antibacterial and nonantibacterial (antifungal, antiviral and anticancer) tetracyclines. Lipophilicity of functional groups and conformations interchangeably are determining rules in biological activities of TCs. Upper peripheral modification region Introduction The number of articles published on tetracycline drugs reached the threshold of 50,000 papers since 1948. Over the last 10 years, technological fields are emerging in bacteriology and cellular physiology of eukaryotic cells. However, Lower peripheral non modifiable region chemical mechanisms of tetracyclines are not completely understood as for their action in human cells and to this day, no (Q)SAR model Figure 1. Structure-Activity-Relationship (SAR) of Tetracyclines (TCs). Shaded: contact region with 30S is validated without doubts. Tetracyclines were rRNA. In blue polygonal same Anthracycline region. first discovered by Dr. Benjamin Dugger of Lederle Laboratories in the mid 1940s as the fermentation product of an unusual golden- colored soil bacterium aptly named Corresponding author Tel/FAX Streptomyces aureofacians 1. Tetracyclines (TCs) (001)514.913.1983. [email protected] are a class of antibiotics able to inhibit protein synthesis in gram positive and gram negative Parkinson and others neurodegeneration bacteria by preventing the attachment of diseases; (IV) antiviral and anticancer 15-17 ; (V) aminoacyl-tRNA to the ribosomal acceptor (A) Tet repressor controlled gene switch 18 ; site .2 . This mechanism has been confirmed by X- ray cristallography 3. TCs bind specifically to the Antibacterial use bacterial ribosome and not with specifically I. Currently, as a consequence of their large use, eukaryotic ribosomes. TCs belong to a notable bacteria has developed TC resistance (efflux class of biologically active and commercially pump type) as opposed to the oldest compounds. valuable compounds. This fact may be simply Medicinal chemists with the intention to illustrated by mentioning the most important optimize structure and improve the antibacterial clinical application of TCs, their employment as power have successfully introduced an alkaline broad antimicrobial-spectrum antibiotics for 4 group on C-9 of minocycline skeleton, starting human and veterinary use . While discovered as a compound from total synthesis: Tigecycline and initially developed as antibiotics, they also (a patent of Pfizer and Wyeth, available in hold promise as non-antibiotic compounds for therapy from 2005). Searching for new future study and use. Tetracyclines, as dynamics molecules, it is not only important to study the entities, possess unique chemical and biological binding of drugs specifically to bacterial characteristics that may explain their ability to ribosome, but also to understand how the interact with so many different cellular targets, 5 skeleton of tetracycline can act like chelator and receptors and cellular properties . The discovery 19 ionophore . Moreover, the next generation of of new uses of tetracyclines and their novel antibacterial tetracyclines, is in progress, highly biological properties against both prokaryotes specific for bacterial species and with new and eukaryotes is currently under investigation groups and new rings on the classical skeleton 20. by numerous scientists throughout the world. Mechanism of action of TCs is divide in TCs as drugs show only few side effects: One is “typical”, if they act as bacteriostatic, or chelation of calcium and subsequent “atypical” if they act as batericidic. Typical TCs intercalation in bones and teeth and the other is bind specifically the bacterial ribosomal an action like photosensitizing drugs, given their subunits. All of them that don’t have ribosomal phototoxic action on keratinocytes and as primary target are consider atypical. fibroblasts. The mechanism of phototoxicity in 6 Moreover, these atypical mechanism of action vitro and in vivo is not yet entirely clear. are very toxic both for prokaryotic and Pharmacological activities eukaryotic (even for mammalian cells). Until now all TCs used in therapy are broad-spectrum The therapeutic uses are as follows: antibacterial against microbial agents, but researchers are and non-antibacterial. In the literature, these developing a platform to introduce in therapy uses fall into five main categories, namely: (I) only novel TCs with a narrow-spectrum for newer and more potent tetracyclines use in infection diseases. anitibacterial resistance 7, (II) the nonantibacterial uses of tetracyclines targeted toward: a) inflammation 8 and arthritis 9-12 ; (III) in neurology: a) in tissue destructive diseases acting like antifibrilogenics 13 ; b) inhibiting caspase-1 and caspase-3 expression in Hungtington disease 14 ; c) ischemia; d) Scheme 1 . Wide-spectrum of activities of tetracyclines (TCs) as antibiotic drugs. TCs are subdivided in: antibacterial (with typical and atypical mechanism of action), antifungal and antineoplastic. During the last 60 years were introduce some chemical modification around the four condensaded rings to obtain more therapeutic selectivity. Anthracyclines, Chemical Modified Tetracyclines, Glycilcycline and Aminomethylcycline are considered members of the same family of chemicals structurally correlated to Tetracycline. Non-antibacterial use cells and subsequently prevented virus-induced apoptosis 32 . II . Both laboratory and clinical studies have investigated the anti-Inflammatory properties of V. The tetracycline-controllable expression tetracyclines, acting as inhibitor of proliferation system offers a number of advantages: strict of lymphocytic9, suppression of neutrophilic on/off regulation, high inducibility, short 10 11 migration , inhibition of phospholipase A 2 and response times, specificity, no interference with accelerated degradation of nitric oxide the cellular pathway, bioavailability of a non- synthetase 12 . toxic inducer, and dose dependence. The tet-off system 33 , which uses the tetracycline-responsive III . In recent times, starting from the end of the transcriptional activator (tTA), and the tet-on 21 90s , TCs have showed to be anti-caking of β- system 34 , which uses the reverse tetracycline- amyloid protein and therefore useful in the responsive transcriptional activator (rtTA), treatment of neurodegenerative diseases like provide respectively negative and positive 22-23 Alzheimer’s and the Prion Diseases . In control of transgene expression. particular, Minocycline reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic windows24. Also, Minocycline inhibits caspase-3 expression and Classification of Tetracyclines delays mortality in a transgenic mouse model of 25 Historically, Tetracyclines are divided into Huntington Disease . Researchers focused on First generation if they are obtained by the mechanisms of intracellular pathway biosynthesis: Tetracycline; Chlortetecycline; communication and genetic control leading to 26 Oxytetracycline; Demeclocycline; Second the attenuation of microglia activation and 27 generation if they are derivatives of semi- protection of Schwann cells . synthesis: Doxycycline; Lymecycline; IV . In the same way that tetracyclines act as pro- Meclocycline; Methacycline; Minocycline; apoptotic in neuronal cells, they act in peripheral Rolitetracycline; And Third generation if they metastasis of generalized tumor. Experimental are obtained from total synthesis: Tigecycline. data using various carcinoma cell lines and However, some researchers consider Tigecycline animal carcinogenesis models showed that a part from Tetracyclines drugs as a new family doxycycline, minocycline and chemical of antibacterial called Glycylcycline. The modified tetracyclines (CMTs) inhibit tumor present paper introduces a new schematic point growth by inhibiting matrix metalloproteinase of view about the denomination and the (MMPs) and by having a direct effect on cell classification of Tetracycline-Structure-Based proliferation 16-17 . The first use of tetracyclines drugs. In the years to come, new TCs, that now in viral infections was reported by Lemaitre in are advanced in the clinical trials (Phase III of 1990 30 . Minocycline and doxycycline imparted Pharmaceutical Trials Protocol), will be in which case, protection against human available in therapy. TCs obtained via total immunodeficiency

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