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Emerging Highlights on Natural Prodrug Molecules with Multifarious Therapeutic Perspectives
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Mojabir Hussen Ansari, Vaibhav Shende, Debarshi Kar Mahapatra
The natural product exists everywhere. When we think about the natural product, the first thing comes into mind is a large plant, but shrubs and bioactive animal products or even bacteria, fungi, yeast, molds that also provide an excellent source of material in modern therapeutics. The products that are naturally derived play an important role in the development of synthetic prodrug molecules for various therapeutic purposes. In this chapter, 15 prodrugs from natural resources were discussed comprehensively. Various synthetic prodrugs have been discovered so far with several added advantages but prodrugs from natural sources have fewer side effects as compared to the synthetic prodrugs along with easy accessibility. However, it will take years to receive attention toward these products to come into mainstream pharmacotherapeutics.
Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
There are several examples of bioreductive prodrugs, some of which are either in clinical use or are undergoing preclinical or clinical studies. The first group consists of molecules containing quinone moieties, the best-known member of which is mitomycin C which contains an indolequinone nucleus. The experimental agent EO9 is also a member of this family. The second group of bioreductive agents includes molecules based on aromatic N-oxides (e.g., tirapazamine) and aliphatic N-oxides (e.g., AQ4N). The latter has been evaluated in the clinic, and pharmacodynamic and pharmacokinetic data suggest that it is working through a bioreductive mechanism although clinical benefit was not sufficient to warrant further development. A third group of experimental agents include molecules containing nitroheterocycles such as CB-1954, SN-23862, NITP, SR4554 and pimonidazole, the latter of which has been evaluated in the clinic as a hypoxia marker. Mitomycin is arguably the most important bioreductive agent as it is approved and extensively used in the clinic worldwide. AQ4N is one of the best-known experimental bioreductive agents, although it did not reach the approval stage. Both of these agents are described below in more detail as they are the best examples of approved and experimental agents of this type.
Principles and Methods of Ocular Pharmacokinetic Evaluation
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
Increasingly, prodrugs are being used experimentally, as well as clinically, to reduce side effects. For example, one of the difficulties with the potential topical use of delta-9- tetrahydrocannabinol is the systemic absorption that occurs. This could lead to undesirable effects. With the use of a water-soluble prodrug, a maleate salt of (+)-delta-6-tetrahydrocannabinol dimethylheptyl, Mechoulam et al.129 overcame this problem by using the native corneal enzymes to convert this water-soluble form into a lipid-soluble drug. Once the drug enters the epithelium and becomes hydrophobic, there is no loss into the watery tear film. Thus, the drug is trapped and remains exclusively in ocular tissues. Use has been made of this approach by using the plentiful esterases in the cornea to transform prodrugs into active compounds that can then enter both anterior segment tissues and the more posterior ocular tissues.130
Targeted drug delivery strategy: a bridge to the therapy of diabetic kidney disease
Published in Drug Delivery, 2023
Xian Chen, Wenni Dai, Hao Li, Zhe Yan, Zhiwen Liu, Liyu He
The definition of prodrug raised by Albert can best summarize its features, that is ‘Prodrugs are chemicals with little or no pharmacological activity, undergoing biotransformation to a therapeutically active metabolite (Albert, 1958)’. There are two kinds of prodrugs, the bioprecursors and the carrier-linked prodrugs. Bioprecursors, including quinones, nitroarenes, N-oxides and amidoximes, do not have carriers and they can be activated by hydration, while the carrier-linked prodrugs are always esters activated by enzymatic hydrolysis (Testa, 2009). Gluconeogenesis is an important cause of hyperglycemia in type 2 DM. Researchers synthesized a small molecular 4-[2-(1H-indol-3-yl) vinyl] quinoline (IVQ) as a prodrug, which can suppress hepatic gluconeogenesis and ameliorate hyperglycemia without the cardiovascular side effects and genotoxicity in type 2 DM rats (Zhou et al., 2019). Bardoxolone methyl (CDDO-Me) exhibited a promising therapy for diabetic nephropathy in clinical trials, but the cardiac toxicity restrained its application. Therefore, a series of prodrugs, just as Cathepsin B (CTSB)-α-cyano-α, β-unsaturated ketone (CUK)-polyethylene glycol (PEG), were formed, making CDDO-Me without the active CUK part exposure in order to reduce the side effects of the treatment (Liu et al., 2022).
Advances in prodrug design for Alzheimer’s disease: the state of the art
Published in Expert Opinion on Drug Discovery, 2022
Valentin Travers--Lesage, Serge M. Mignani, Patrick Dallemagne, Christophe Rochais
Since the early seventies, the prodrug technology drugs have gained attention and remains an important challenge. The future will be to develop new types of prodrugs based on new available organic reactions as well to include the prodrug approach in modern drug discovery and development. The exact control of the rate of prodrug cleavage from its parental drugs represents also a challenge for the chemists because it is controlled, for instance, by the abundance or not of certain enzymes in the route. Investigation to assign the factors in the determination of the reaction rate by computational chemistry studies represents also a way to design new prodrug approaches which are being considered in a very early stage of the drug development process. To conclude, we fully agree with Albert Einstein about ‘imagination is more important than knowledge’ (1931).
How can we improve the design of small molecules to target thioredoxin reductase for treating cancer?
Published in Expert Opinion on Drug Discovery, 2021
Prodrugs are molecules that are activated and converted into pharmacologically active drugs after administration. As TrxR is generally overexpressed in different types of tumors, the development of TrxR-dependent prodrugs is also a strategy to treat tumors. In our efforts to develop the TRFS series fluorescent probes of TrxR, we disclosed that the 1,2-dithiolane (five-membered cyclic disulfide) scaffold could be reduced by TrxR exclusively [15,16]. Based on this discovery, we prepared a first TrxR-dependent prodrug S-Gem and demonstrated that S-Gem shows TrxR-dependent cytotoxicity [17]. Compared to the inhibition of TrxR for cancer treatment, the success of S-Gem provides a completely new strategy to develop therapeutic molecules that target TrxR. We expect that the 1,2-dithiolane unit may be a general scaffold to construct TrxR-dependent prodrugs.