Thalidomide contergan annotated collection of links. Chemistry, mechanisms of action, therapeutic potential and antiangiogenic properties in multiple myeloma article in current medicinal chemistry 2425 june 2017. Thalidomide and its derivatives are currently under investigation for their antiangiogenic, immunomodulative, and anticancer properties. Yashoda hematology clinic, pune mangalmurti complex, 109, first floor, near hirabaug chowk, lokmanya bal gangadhar tilak road, pune, maharashtra, india. Described herein is an efficient microwave irradiation green synthesis method that allows preparation of thalidomide and its analogs in a onepot. Current topics in medicinal chemistry 2019, 19 15, 12761288. Current methods used to synthesize these compounds involve multiple steps and extensive workup procedures. The drug appeared to be unusually safe, with few side effects and little or no toxicity even at high doses. Introduction to stereochemistry structural constitutional isomers compounds of the same molecular formula with different connectivity structure, constitution conformational isomers compounds of the same structure that differ in rotation around one or more single bonds configurational isomers or stereoisomers compounds of the same structure that differ in one or more. Drug racemization and its significance in pharmaceutical. Pdf in the past 50 years, thalidomide has undergone a remarkable metamorphosis from a notorious drug. Thalidomide was introduced in the 1950s as a sedative that was prescribed for nausea and insomnia in pregnant women. Medicinal chemistry chem 458658 chapter 2 drug structure and solubility bela torok department of chemistry university of massachusetts boston boston, ma 1.
Consequently, the design and synthesis of configurationally stable analogs of thalidomide continue to be an important area of research in bioorganic and medicinal chemistry. Robey,3 karl werbovetz,1 andrew lewis,1 and chenglong li1 1division of medicinal chemistry and pharmacognosy, college of pharmacy, the ohio state university, columbus, ohio and. Enantiomerization mechanism of thalidomide and the role of. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum enl and mutiple myeloma and effectively reduces tumor necrosis factor. The emergence of thalidomide as a treatment for myeloma. Wilson and gisvolds textbook of organic medicinal and pharmaceutical chemistry, lippincott, philadelphia 2. Pdf thalidomidea notorious sedative to a wonder anticancer. Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on stereoisomers, which by definition have the same molecular formula and sequence of bonded atoms constitution, but differ in the threedimensional orientations of their atoms in space. Teaching chemistry through the jigsaw strategy example 1. Thalidomide is a synthetic derivative of glutamic acid alphaphthalimidoglutarimide with teratogenic, immunomodulatory, antiinflammatory and antiangiogenic properties. Medicinal, agricultural, synthetic applications and natural products chemistry provides a comprehensive overview of imides being developed as pharmaceuticals or experimental therapeutics.
To be empowered to play an active role in your own medical care and to make. These enantiomers rapidly get interconverted under physiological conditions thalidomide is sparingly soluble in water and ethanol, which. By highlighting the concepts and skills related to drug discovery, stevens deepens readers understanding of the knowledge and techniques necessary for their careers. Structural differences, aggregation states, and log p values of 1, 2 and their enantiomers suggest the supposed mechanisms of sde of 1 and 2. It was introduced in germany in 1957 as a sedative and hypnotic and was marketed over the counter largely as a drug for treating morning sickness in pregnant women. We have identified the two most plausible interconversion pathways for isolated thalidomide. Chemistry of thalidomide thalidomide, anphthalimido glutarimide, consists of ringed structure with an asymmetric carbon in the glutarimide ring. Atropisomerism is a dynamic type of axial chirality that is ubiquitous in medicinal chemistry. Concise asymmetric synthesis of configurationally stable 4. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased tnf. We first aim to give an overview of the most conventional aspects of thalidomide. Learn vocabulary, terms, and more with flashcards, games, and other study tools.
National library of medicines medical subject headings. In late 1950s, the discovery of its sedative effects led to the introduction of thalidomide to the public as a drug for treating morning sickness. One class of thalidomide analogues is called immunomodulatory drugs. For decades, thalidomide has been highlighted as a typical example of risk associated with the old drug discovery paradigm of phenotypic driven drug discovery. The renantiomer, shown in the figure, has sedative effects, whereas the s isomer is teratogenic. In this study, two thalidomide analogs, gi16 and sc15, were. The computations indicated that thalidomide 1 changes to become more hydrophilic by the formation of its dimer, while fluorinated thalidomide 2 becomes more hydrophobic with dimerization. Hartmann, department of protein evolution, max planck institute for developmental biology, maxplanckring 5, 72076. Role of thalidomide in treatment of beta thalassemia.
The chiral inversion of thalidomide is thus subject to specific and general base catalysis, and it is suggested that the ability of hsa to catalyze the reaction is due to the basic groups of the amino acids arg and lys and not to a single catalytic site on the macromolecule. Thalidomide victims hope that pharmaceutical companies could discover an analogue with the positive clinical effects of thalidomide but without its harmful side effects. Thalidomidea notorious sedative to a wonder anticancer drug. Thalidomide is an immunomodulatory agent with antiinflammatory activity, however it may also cause serious side effects. Thalidomide was placed on the market in germany as an overthecounter sedativehypnotic drug in october 1957 and was subsequently sold in at least 46 countries under 51 trade names. Thalidomide was developed in west germany in the mid1950s and was found to induce drowsiness and sleep. Thalidomide is not a drug that that impinges on just one biological pathway. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited tnf. A naturally produced chemical released by the body, or a substance.
Pharmaceutical and medicinal chemistry david g watson. Thalidomide, innthalidomide european medicines agency. New thalidomidelike therapy hijacks cells trashdisposal system. Denovo design of cereblon crbn effectors guided by. Thalidomide is racemic it contains both left and right handed isomers in equal amounts. Selfdisproportionation of enantiomers of thalidomide and. Thalidomide immunoprin is an immunomodulatory drug effective in the treatment of. Patients should be instructed never to give this medicinal product to another person. Recent studies on the thalidomide and its derivatives. A thalidomide analogue with in vitro antiproliferative. That complexity could explain its multifaceted effectsfrom its. In the following few years, about 10,000 infants worldwide were born with phocomelia, or limb malformation.
A number of developments took place in the 1960s, which changed medicinal chemistry. Deeper studies about thalidomide have started on the 90s, when some of. Improvements in solubility and stability of thalidomide. Pdf, epub, full text, audio unceasing customer service. Tylenol and thalidomide tragedy free download as powerpoint presentation. Whether youve loved the book or not, if you give your honest and detailed thoughts then people will find new books that are right for them.
Thalidomide is in clinical use for the treatment of graft. However, it was found to be the cause of severe birth defects in children whose mothers had taken the drug in their first trimester of pregnancy. Sackett,2 zhigen hu,1 jennifer zink,1 jiandong zhi,1 dena freeman,1 robert w. The enantiomers are converted to each other in vivo.
Thalidomide, compound in medicine initially used as a sedative and an antiemetic until the discovery that it caused severe fetal malformations. A useful tool for pharmaceutical sciences and drug development. In 1957, a pharmaceutical company in west germany introduced a new drug to the market. Annotated collection of english and german web resources providing information on the drugs physicochemical properties, effects, side effects, the german contergan disaster in the early 1960s, and the current use of thalidomide. A thalidomide analogue with in vitro antiproliferative, antimitotic, and microtubulestabilizing activities puikai li,1 bulbul pandit,1 dan l. Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized.
Annalisa mercurio, giulia adriani, alessia catalano, alessia carocci, luigia rao, giovanni lentini, maria m. The modern drug discovery process delivers a comprehensive introduction to medicinal chemistry at an appropriate level of detail for a diverse range of readers. Stability study of a thalidomide suspension request pdf. The history of medicinal chemistry medicinal chemistry. White opaque capsules marked thalidomide celgene 50 mg. Pdf thalidomide is responsible for the biggest medical disaster in history, causing severe birth defects in more than 0 children, globally. Carlos menendez, in medicinal chemistry of anticancer drugs, 2008.
Thalidomide analogs and pde4 inhibition, bioorganic. New thalidomidelike therapy hijacks cells trashdisposal. New compounds derived from thalidomide effective in modulating inflammatory responses and having. Thalidomide ch10n2o4 cid 5426 structure, chemical names, physical and chemical properties. There are several examples of stable atropisomeric us fdaapproved drugs and experimental compounds, and in each case the atropisomers of these compounds possess drastically different biological activities.
Lessons as lecture 5 related to chirality of drugs 4 lecture 6. Chemistry, mechanisms of action, therapeutic potential and antiangiogenic properties in multiple myeloma, current medicinal chemistry 2017 24. Thalidomide, independently of its teratogenic effects, is one drug able to regulate the immune system. However, the mechanisms underlying its pharmacological action are still under investigation. Identification of a primary target of thalidomide teratogenicity. Low levels of the drug in plasma after oral administration have made an. Most chiral drugs contain one or more chiral centers. Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologicallymediated and infectious diseases, and cancers. Thalidomide acts primarily by inhibiting both the production of tumor necrosis factor alpha tnfalpha in stimulated peripheral monocytes and the activities of interleukins and interferons. R isomer had the desired effect, s isomer was discovered to be teratogenic caused serious fetus. Thalidomide one enantiomer alleviates symptoms of the pregnancy morning sickness, the other enantiomer causes deformities in the limbs of fetus.
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