Ornithine Decarboxylase Inhibition: A Strategy to Combat Various Diseases

Somani, Rakesh R.; Priyanshu, R; Kandpile, Pooja S

doi:10.2174/1389557517666170927130526

Cited by 20 publications

(15 citation statements)

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“…For instance, in addition to NO synthesis it may affect the urea cycle as well as protein and polyamine synthesis, potentially affecting ECM treatment outcome. Polyamines, for instance, have been shown to be important for malaria parasites and also in the physiology and metabolism of the nervous system 46,47 . Both human and mouse cerebral malaria cause depletion of arginine, citrulline and ornithine, due to a marked decrease in arginine appearance 9 .…”

Section: Discussionmentioning

confidence: 99%

L-arginine supplementation and thromboxane synthase inhibition increases cerebral blood flow in experimental cerebral malaria

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Estato

Malvar

et al. 2019

Sci Rep

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Cerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia, tissue hypoxia and ultimately death. Cerebral blood flow (CBF) involves NO and other pathways, including arachidonic acid (AA)-derived metabolites. Here we show that mice with experimental cerebral malaria (ECM) by P. berghei ANKA showed marked decreases in CBF (as assessed by laser speckle contrast imaging - LSCI) and that administration of L-arginine supplementation (50 mg/kg) and/or of the thromboxane synthase inhibitor Ozagrel (100 mg/kg) induced immediate increases in CBF. L-arginine in combination with artesunate (32 mg/kg) induced immediate reversal of brain ischemia in the short-term (1 hour), but the effect subsided after 3 and 6 hours. Neither L-arginine nor Ozagrel reversed blood brain barrier breakdown. Mice with ECM showed brain levels of selected AA-derived metabolites with a vasoconstrictor profile, with increased levels of 8-isoprostanes, 20-HETE and 14,15-DHET, whereas mice infected with a non-ECM-inducing strain of P. berghei (NK65) showed a vasodilator profile, with normal levels of 20-HETE and 14,15-DHET and increased levels of PGE2. L-arginine is capable of partially reversing cerebral ischemia and AA metabolites may play a role in the cerebrovascular dysfunction in ECM.

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Section: Discussionmentioning

confidence: 99%

L-arginine supplementation and thromboxane synthase inhibition increases cerebral blood flow in experimental cerebral malaria

Moreira

Estato

Malvar

et al. 2019

Sci Rep

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“…While quiescent cells show low ODC activity and putrescine levels, actively dividing cells exhibit increased ODC activity [ 8 , 9 , 10 , 11 ]. Enzyme activity is high during late G1 phase before DNA synthesis begins and again in the G2/M transition phase [ 8 , 9 , 10 , 11 ]. An essential downstream function of the polyamine pathway is the hypusination and activation of eukaryotic initiation factor eIF5A, vital for protein synthesis and cellular proliferation [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases

LoGiudice

Abuan

et al. 2018

Medical Sciences

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The fluorinated ornithine analog α-difluoromethylornithine (DFMO, eflornithine, ornidyl) is an irreversible suicide inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis. The ubiquitous and essential polyamines have many functions, but are primarily important for rapidly proliferating cells. Thus, ODC is potentially a drug target for any disease state where rapid growth is a key process leading to pathology. The compound was originally discovered as an anticancer drug, but its effectiveness was disappointing. However, DFMO was successfully developed to treat African sleeping sickness and is currently one of few clinically used drugs to combat this neglected tropical disease. The other Food and Drug Administration (FDA) approved application for DFMO is as an active ingredient in the hair removal cream Vaniqa. In recent years, renewed interest in DFMO for hyperproliferative diseases has led to increased research and promising preclinical and clinical trials. This review explores the use of DFMO for the treatment of African sleeping sickness and hirsutism, as well as its potential as a chemopreventive and chemotherapeutic agent against colorectal cancer and neuroblastoma.

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“…The polyamine biosynthetic pathway is initiated by enzyme ornithine decarboxylase (pyridoxal-5'-phosphate-dependent enzyme). Therefore, inhibition of ornithine decarboxylase may be the essential approach for the management of cancer and other various diseases: malaria or African sleeping sickness, neglected tropical diseases [43][44][45][46][47]. This situation prompts an intensive search for new ornithine-based pharmaceuticals.…”

Section: Role Of Ornithine In Polyamine Biosynthesismentioning

confidence: 99%

A Supramolecular Approach to Structure-Based Design with A Focus on Synthons Hierarchy in Ornithine-Derived Ligands: Review, Synthesis, Experimental and in Silico Studies

Bojarska

Remko²,

Breza

et al. 2020

Molecules

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The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems is controlled by non-covalent interactions to a very large extent. The latter are prone to extensive cooperation and like a virtuoso play a symphony of life. Thus, the design of effective ligands should be based on thorough knowledge on the interactions at either a molecular or high topological level. In this work, we emphasize the importance of supramolecular structure and ligand-based design keeping the potential of supramolecular H-bonding synthons in focus. In this respect, the relevance of supramolecular chemistry for advanced therapies is appreciated and undisputable. It has developed tools, such as Hirshfeld surface analysis, using a huge data on supramolecular interactions in over one million structures which are deposited in the Cambridge Structure Database (CSD). In particular, molecular interaction surfaces are useful for identification of macromolecular active sites followed by in silico docking experiments. Ornithine-derived compounds are a new, promising class of multi-targeting ligands for innovative therapeutics and cosmeceuticals. In this work, we present the synthesis together with the molecular and supramolecular structure of a novel ornithine derivative, namely N-α,N-δ)-dibenzoyl-(α)-hydroxymethylornithine, 1. It was investigated by modern experimental and in silico methods in detail. The incorporation of an aromatic system into the ornithine core induces stacking interactions, which are vital in biological processes. In particular, rare C=O…π intercontacts have been identified in 1. Supramolecular interactions were analyzed in all structures of ornithine derivatives deposited in the CSD. The influence of substituent was assessed by the Hirshfeld surface analysis. It revealed that the crystal packing is stabilized mainly by H…O, O…H, C…H, Cl (Br, F)…H and O…O interactions. Additionally, π…π, C-H…π and N-O…π interactions were also observed. All relevant H-bond energies were calculated using the Lippincott and Schroeder H-bond model. A library of synthons is provided. In addition, the large synthons (Long-Range Synthon Aufbau Module) were considered. The DFT optimization either in vacuo or in solutio yields very similar molecular species. The major difference with the relevant crystal structure was related to the conformation of terminal benzoyl C15-C20 ring. Furthermore, in silico prediction of the extensive physicochemical ADME profile (absorption, distribution, metabolism and excretion) related to the drug-likeness and medicinal chemistry friendliness revealed that a novel ornithine derivative 1 has the potential to be a new drug candidate. It has shown good in silico absorption and very low toxicity.

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Ornithine Decarboxylase Inhibition: A Strategy to Combat Various Diseases

Cited by 20 publications

References 0 publications

L-arginine supplementation and thromboxane synthase inhibition increases cerebral blood flow in experimental cerebral malaria

L-arginine supplementation and thromboxane synthase inhibition increases cerebral blood flow in experimental cerebral malaria

Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases

A Supramolecular Approach to Structure-Based Design with A Focus on Synthons Hierarchy in Ornithine-Derived Ligands: Review, Synthesis, Experimental and in Silico Studies

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