Papers by Yousef Najajreh
IntechOpen eBooks, Dec 21, 2022
Diazine alkaloid (pyridazine, pyrimidine and pyrazine) scaffold, a widespread two-nitrogen contai... more Diazine alkaloid (pyridazine, pyrimidine and pyrazine) scaffold, a widespread two-nitrogen containing compounds in nature (DNA, RNA, flavors, and fragrances), constitutes a central building block for wide range of pharmacological applications. Diazines are reported to exhibit antimetabolite (antifolate and), anticancer, antibacterial, antiallergic, tyrosine kinase, antimicrobial, calcium channel antagonistic, anti-inflammatory, analgesic, antihypertensive, antileishmanial, antituberculostatic, anticonvulsant, diuretic and potassium-sparing, to antiaggressive activities. Pyridazine (1,2-diazine), pyrimidine (1,3-diazine) and pyrazine (1,4-diazine) are found as mono-systems, fused or annulated in pharmaceutical, agrochemical or materials. These six-membered heterocyclic aromatic moieties defined as privileged scaffolds constitute diverse chemical structures and as such hold substantial interest for organic, medicinal and biological chemists. This chapter will focus on elaboration of the different synthetic approaches applied in preparing pharmacologically active decorated diazines with special care on pyrimidines (non-fused substituted forms) that are endowed with clinical applications. Synthetic approaches applied in preparing selected FDA approved drugs with pyrimidine as a central unit bearing different substituents will be intensively explored. Special attention will be given to novel synthetic methodologies that served molecules with improved druglikeness and ADME-Tox properties.
Cancer Research, Jun 15, 2022
The inherent genetic instability of cancer cells and the dependence of many tumor types on oncoge... more The inherent genetic instability of cancer cells and the dependence of many tumor types on oncogenic drivers contribute selectivity of anticancer agents against tumor cells. That selectivity is limited, and toxicity to normal cells remains a major limitation to the success of chemotherapy. To increase selectivity by exploiting cancer cell genetic instability, we demonstrated that the small molecule IBR2 (an inhibitor of the DNA repair protein RAD51) enhanced cytotoxicity of numerous anticancer drugs including agents that do not directly target DNA (J Pharmacol Expt Ther, 364: 46-54, 2018. doi.org/10.1124/jpet.117.241661). We demonstrated the ability of IBR2 and a derivative [IBR120, (R)-3-(2-(benzylsulfonyl)isoindolin-1-yl)-1h-indole] to synergistically inhibit proliferation of a wider range of cancer cell lines in combination with a broad range of anticancer drugs (Proc. Amer. Assoc. Cancer Res., 60: Abst. 3057, 2019). To improve the activity and potentially increase selectivity for inhibiting RAD51, modifications were made to the structure of IBR120 using a virtual drug-protein docking program, yielding the compound JKYN-1. JKYN-1 inhibits proliferation of cancer cell lines approximately 5 times more strongly than IBR120. Given the potential importance of combining JKYN-1 with targeted anticancer drugs to increase therapeutic index, and the synergy previously observed between IBR120 and agents targeted against specific tumor types, JKYN-1 was tested in combination with targeted agents against a panel of tumor cell lines. Four- to five-day drug exposures were conducted in 96-well plates. Relative cell density determined using vital stains (alamarBlue©, neutral red) was reported as a percent of the fluorescence/absorbance of control cultures. Cell lines were representative of tumors from breast (MCF-7), prostate (DU145, LNCaP), stomach (N87), pancreas (PANC-1, Capan-1, Capan-2) and lung (A549b, H1650). The chemotherapy agents included inhibitors of epidermal growth factor receptor (osimertinib, afatinib), other tyrosine kinases (regorafenib, imatinib), sex steroid receptors (4-OH-tamoxifen, enzalutamide), and microtubule function (docetaxel). To improve solubility, a methylsulfonate salt of JKYN-1 was used for most experiments. JKYN-1-mesylate decreased the concentration of drugs that inhibited proliferation by 50% (IC50) by up to 90%, depending on the drug and cell line, indicating synergy between the agents. There were some combinations in which additivity but no synergy was observed, indicating selectivity for this interaction. Individual combinations will be presented. The ability of JKYN-1 to enhance antiproliferative activity of a wide variety of anticancer agents, and its potential selectivity for cancer cells, make possible the future use of RAD51 inhibitors as systemic therapy potentiators to improve clinical outcomes. Citation Format: Peter J. Ferguson, Mark D. Vincent, Yousef Najajreh, Brian Shilton, Stephen Ritter, Rima Al-awar, Richard Marcellus, Mohammed Mohammed, Methvin Isaac, James Koropatnick. Synergistic antiproliferative activity of novel RAD51 inhibitor JKYN-1 and its mesylate salt with standard-of-care cancer drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 346.
Journal of Medicinal Chemistry, Oct 30, 2002
The synthesis, chemical characterization, and interaction with cells of new sterically hindered t... more The synthesis, chemical characterization, and interaction with cells of new sterically hindered trans-and cis-diaminedichloroplatinum(II) complexes are described. The amine ligands include monofunctional piperidine (pip) and piperazine (pz). The poor solubility of trans-...
Chemistry & Biodiversity
Introduction – The obesity pandemic is multifactorial. Nutritional, pharmacologic and surgical in... more Introduction – The obesity pandemic is multifactorial. Nutritional, pharmacologic and surgical interventions are limited in reach and efficacy, raising need for new therapeutics.Aims – Characterization of anorexigenic and cognitive effect and central mechanism of action of novel N‐acylethanolamide derivatives.Methods – Sabra mice divided to similar experimental groups, injected IP with: oleyl‐L‐leucinolamide (1 A), linoleyl‐L‐leucinolamide (4 A), linoleyl‐L‐valinolamide (5 A), oleyl‐oxycarbonyl‐L‐valinolamide (1 B), oleyl‐oxycarbonyl‐D‐valinolamide (2 B), oleylamine‐carbonyl‐L‐valinolamide (3 B), oleylamine‐carbonyl‐D‐valinolamide (4 B), and oleyl‐L‐hydroxyvalineamide (5 B). Control group with vehicle. Body weight and food consumption followed for 39 days. Motor activity and cognitive function by open field test and eight‐arm maze. Mice sacrificed and mechanism of action investigated by qPCR. The genes analyzed involved in energy balance and regulation of appetite. Catecholamines an...
Related Article: Y.Najajreh, Y.Ardeli-Tzaraf, J.Kasparkova, P.Heringova, D.Prilutski, L.Balter, S... more Related Article: Y.Najajreh, Y.Ardeli-Tzaraf, J.Kasparkova, P.Heringova, D.Prilutski, L.Balter, S.Jawbry, E.Khazanov, J.M.Perez, Y.Barenholz, V.Brabec, D.Gibson|2006|J.Med.Chem.|49|4674|doi:10.1021/jm060238j
2016 AAAS Annual Meeting (February 11-15, 2016), Feb 14, 2016
Journal of Inorganic Biochemistry, 2005
We have evaluated the cytotoxic properties against the protozoan Leishmania infantum of four wate... more We have evaluated the cytotoxic properties against the protozoan Leishmania infantum of four water soluble cationic trans-Pt(II)Cl 2 compounds containing as inert groups NH 3 and piperazine (1), 4-picoline and piperazine (2), n-butylamine and piperazine (3), and NH 3 and 4-piperidino-piperidine (4). The leishmanicidal activity of compounds 3 and 4 against promastigotes of the parasite Leishmania infantum was 2.5-and 1.6-times higher than that of the cytotoxic drug cis-diamminedichloroplatinum(II), respectively. Interestingly, compounds 3 and 4 produce in Leishmania infantum promastigotes a higher amount of programmed cell death than cisplatin, which is associated with cell cycle arrest in G2/M. In contrast to cis-diamminedichloroplatinum(II), binding of compounds 3 and 4 to calf thymus DNA induces conformational changes more similar to those of trans-diamminedichloroplatinum(II) that may be attributed to denaturation of the double helix. Similarly to cis-diamminedichloroplatinum(II) and trans-diamminedichloroplatinum(II), the interaction of compounds 3 and 4 with ubiquitin results in an increase of the a-helix content of the protein as observed by circular dichroism spectroscopy. However, fluorescence studies indicate that compounds 3 and 4 produce a decrease in the fluorescence of the tyrosine 59 residue of ubiquitin higher than both cis-diamminedichloroplatinum(II) and trans-diamminedichloroplatinum(II). Altogether, our results suggest that the biochemical mechanism of cytotoxic activity of compounds 3 and 4 against Leishmania infantum must be different from that of cis-diamminedichloroplatinum(II). To the best of our knowledge, compounds 3 and 4 are the first reported trans-platinum complexes that show antiparasitic activity.
Cancer Research, 2021
Despite the innovations in chemotherapeutic treatment of pancreatic cancer, the generally poor ou... more Despite the innovations in chemotherapeutic treatment of pancreatic cancer, the generally poor outcome of this disease begs the search for novel targets. RAD51 is a critical component of homologous recombination DNA repair, binding with BRCA2 and forming polymeric filaments essential for its function. RAD51 is often elevated in cancer cells compared to normal cells, particularly in pancreatic cancer: RAD51 is a negative prognostic biomarker and promotes tumor cell proliferation in that disease (Cancer Cell Int 19: 356, 2019; doi: 10.1186/s12935-019-1077-6). Therefore, RAD51 is an attractive target for anticancer treatment in that its elevated level and activity in tumor cells provide a potential level of selectivity for such an agent, increasing the therapeutic index. We demonstrated previously that novel inhibitors of RAD51, IBR2 [2-(Benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline] and IBR120 (an isoindolinyl derivative of IBR2) (Eur J Med Chem. 96:196-208, 2015; doi: 10....
European Journal of Immunology, 2020
CD5 is expressed on T cells and a subset of B cells (B1a). It can attenuate Tcell receptor (TCR) ... more CD5 is expressed on T cells and a subset of B cells (B1a). It can attenuate Tcell receptor (TCR) signalling and impair cytotoxic T lymphocyte (CTL) activation and is a therapeutic targetable tumour antigen expressed on leukemic T and B cells. However, the potential therapeutic effect of functionally blocking CD5 to increase T cell anti-tumour activity against tumours (including solid tumours) has not been explored. CD5 knockout mice show increased anti-tumour immunity: reducing CD5 on CTLs may be therapeutically beneficial to enhance the anti-tumour response. Here we show that ex vivo administration of a function-blocking anti-CD5 monoclonal antibody (MAb) to primary mouse CTLs of both tumour-naïve mice and mice bearing murine 4T1 breast tumour homografts enhanced their capacity to respond to activation by treatment with anti-CD3/anti-CD28 MAbs or 4T1 tumour cell lysates. Furthermore, it enhanced TCR signalling (ERK activation) and increased markers of T cell activation, including proliferation, CD69 levels, interferon-γ production, apoptosis, and Fas receptor and Fas ligand levels. Finally, CD5 function-blocking MAb treatment enhanced the capacity of CD8 + T cells to kill 4T1-mouse tumour cells in an ex vivo assay. These data support the potential of blockade of CD5 function to enhance T cell-mediated anti-tumour immunity. MHC-TCR interaction leads to T cell activation, but CD5 expression in the immunological synapse attenuates it. Functional blockade of CD5 will then enhance T cell activation and antitumor function
Biochemistry, 2003
FIGURE 1: Structures of the platinum complexes.
Journal of Medicinal Chemistry, 2002
Positively charged, water soluble cis/trans-[PtCl 2 (piperazine)(Am1)] (where Am1) NH 3 , n-butyl... more Positively charged, water soluble cis/trans-[PtCl 2 (piperazine)(Am1)] (where Am1) NH 3 , n-butylamine, isopropylamine, 4-picoline, piperidine, and piperazine) has significant cytotoxic activity against cisplatin resistant ovarian cancer cells. The charged complexes are taken up by cancer cells much more rapidly than cisplatin and bind to cellular DNA and to calf thymus DNA much faster than cisplatin or transplatin. The platinum-piperazine complexes bind proteins (ubiquitin and myoglobin) very slowly as compared to cisplatin and to their neutral piperidine analogues. Altogether, the results reported here suggest that combination of positively charged ligands with a trans-Pt(II)Cl 2 center may lead to the discovery of platinum complexes that are able to circumvent cisplatin resistance.
European Journal of Immunology, 2019
It has been demonstrated that partial and transient systemic inactivation of circulating monocyte... more It has been demonstrated that partial and transient systemic inactivation of circulating monocytes by liposomal bisphosphonates (BPs) reduces neointimal hyperplasia and restenosis in animal models (Danenberg et al., 2002; Danenberg et al., 2003a; Danenberg et al., 2003b; Epstein et al., 2007). Restenosis, re-obstruction of the coronary arteries following percutaneuos coronary interventions such as stent angioplasty, can be prevented by diminishing the inflammatory trigger of smooth muscle cells (SMC) proliferation and migration (Libby et al., 1992; Danenberg et al., 2002; Danenberg et al., 2003a; Danenberg et al., 2003b; Colombo and Sangiorgi, 2004; Cohen-Sela et al., 2006). One single IV injection of liposomal formulation containing a BP such as clodronate or alendronate (ALN), at the time of injury, can treat several vessels with a long-term effect and minimal side effects (Danenberg et al., 2002; Danenberg et al., 2003a; Danenberg et al., 2003b; Epstein et al., 2007). The anti-re...
Journal of Bioanalysis & Biomedicine, 2010
Background: A liposomal delivery system requires a complete understanding of the physicochemical ... more Background: A liposomal delivery system requires a complete understanding of the physicochemical characteristics of the drugliposome system in order to predict their behavior and stability in-vitro and in-vivo. Objectives: Develop a rapid and simple experimental method to determine the fractions of the drug, alendronate (ALN), encapsulated and as a free form distributed in the liposomal suspension, and the physical state of the encapsulated drug. Methods: 31 P-NMR measurements utilizing Ga +3 as a shifting reagent in comparison to HPLC determinations, theoretical calculations and differential scanning calorimetry (DSC) studies of various liposomal ALN formulations. Results: The 31 P-NMR demonstrated that titrating liposomal ALN with increasing amounts of Ga +3 induced a signifi cant shift in the exterior fraction without changing the interior fraction. Quantitative determination of the encapsulated and non-encapsulated fractions of ALN has been achieved at Ga +3 concentrations of 3.2-25mM. The DSC study revealed that none of the formulation ingredients is in a solid phase. Conclusions: 31 P-NMR was found to be sensitive enough to allow accurate differentiation of the distributed fractions of ALN, encapsulated and the non-encapsulated free form. Based on theoretical calculations and DSC analysis it can be concluded that ALN is dissolved in the aqueous core of the liposome.
Chemistry and Applications of Benzimidazole and its Derivatives, Oct 2, 2019
Benzimidazole derivatives are known to act against a range of biological targets and thus gained ... more Benzimidazole derivatives are known to act against a range of biological targets and thus gained clinical applications in a wide spectrum of diseases. Few examples of multitargeted benzimidazole derivatives that were reported during the last decade will be described in this chapter. Multitargeting agents for serving the polypharmacology approach to combat shortcomings of the main one-drug-one target main dogma will be briefly explored. In that context, the multitargeting benzimidazole derivatives gain a special attention. This includes discovery (hit-to-lead), structureactivity relationship (SAR), and binding mode of at least one lead (or hit) in each group. Special attention will be given to two structures dovitinib and AT9283 that are reported to exhibit potent in vitro and in vivo activities against a group of kinases and non-kinase target (as shown recently for dovitinib).
![Research paper thumbnail of Ligand effects on the binding of cis- and trans-[PtCl(2)Am(1)Am(2)] to proteins](https://images.weserv.nl/?url=https%3A%2F%2Fattachments.academia-assets.com%2F75556541%2Fthumbnails%2F1.jpg&q=12&output=webp&max-age=110)
As part of a systematic study of the basic principles that govern the formation and reactivity of... more As part of a systematic study of the basic principles that govern the formation and reactivity of Pt-protein adducts, we report the effect of substituting the amine ligand of cis- and trans-[PtCl(2)(NH(3))(2)] complexes with bulkier planar aromatic or nonplanar cyclic amine ligands on the binding properties of the complexes to ubiquitin and to horse heart myoglobin. The ligand replacement had a different effect on the cis or trans isomers investigated. In the cis-Pt complexes, replacing one or both amine ligands by piperidine or 4-picoline dramatically decreased the binding of the complexes to the proteins studied, whereas in the substituted trans-Pt complexes replacement of the amine by a piperidine or 4-picoline increased the binding rate. This behavior may have to do with the different preferred binding sites of the cis- and trans-Pt complexes. The bulkier cis- or trans-Pt complexes investigated also did not display a preference for Met1 of ubiquitin, possibly owing to steric con...
Blood
598 The t(9;22) translocation (Ph+) leads to the formation of the chimeric bcr/abl fusion gene, w... more 598 The t(9;22) translocation (Ph+) leads to the formation of the chimeric bcr/abl fusion gene, which encodes the BCR/ABL fusion protein. Depending on the minor and major breakpoint (m-BCR or M-BCR, respectively) on chromosome 22, either the p185-BCR/ABL (p185) or the p210-BCR/ABL (p210) fusion protein is expressed. In contrast to p210, p185 lacks the putatively oncogenic dbl- and pleckstrin homology domains. In the majority of the cases Ph+ ALL patients harbor the p185, but with increasing age the number Ph+ ALL patients with the p210 increases up to an 40%. Only few functional and biological differences between p185 and p210 are known. Both exhibit a constitutively activated kinase activity responsible for the induction of the leukemic phenotype in contrast to their physiological counterpart, c-ABL, whose kinase activity is finely regulated. One reason is that BCR/ABL “escapes” auto-inhibition mechanisms of c-ABL, such as the allosteric inhibition by “capping”. “Capping” is the pr...
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Papers by Yousef Najajreh