The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N2 and N3 aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N, N’, N”-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using hydrogenolysis gave bis-HOPO chelators N2(etLH)2 and N2(prLH)2, and tris-HOPO chelator N3(etLH)3 in excellent yields. Solution thermodynamic characterization of their complexes with Fe(III) has been accomplished using spectrophotometric, potentiometric and ESI-MS methods. The pKas of N2(etLH)2, N2(prLH)2, and N3(etLH)3, were determined spectrophotometrically and potentiometrically. The Fe(III) complex stability constants for the tetradentate N2(etLH)2 and N2(prLH)2, and hexadentate N3(etLH)3, were measured by spectrophotometric and potentiometric titration, and by competition with EDTA. N3(etLH)3 forms a 1:1 complex with Fe(III) with log β110 = 27.34 ± 0.04. N2(prLH)2 forms a 3:2 L:Fe complex with Fe(III) where log β230 = 60.46 ± 0.04 and log β110 = 20.39 ± 0.02. While N2(etLH)2 also forms a 3:2 L:Fe complex with Fe(III), solubility problems precluded determining log β230; log β110 was found to be 20.45 ± 0.04. The pFe values of 26.5 for N3(etLH)3 and 24.78 for N2(prLH)2 are comparable to other siderophore molecules used in the treatment of iron overload, suggesting that these hydroxypyridinone ligands may be useful in the development of new chelation therapy agents.
The preparation of the new electrophilic iminium ester mesylate salt 5 and its reaction with primary and secondary amines have been investigated. Aniline, t-butylamine, and secondary amines react with 5 via ring opening to give the corresponding HOPO derivatives in high yields. The usefulness of this methodology has been demonstrated by the preparation of two new di-HOPO derivatives 19 and 21. This method allows the introduction of the HOPO ligand onto a variety of amine platforms without the concomitant formation of an amide bond and provides access to HOPO chelators of increased water solubility. KeywordsHydroxypyridinones; synthesis; metal ion chelators; MRI contrast agents; iron overload diseases Chelators carrying the 3-hydroxy-2-pyridinone (3,2-HOPO) ligand, as well as its positional isomers (1,2-HOPO and 3,4-HOPO) have been of interest due to their strong Fe(III) binding properties and potential applications in the treatment of patients suffering from iron overload diseases (β-thalassemia also known as Cooley's Anemia). 1 Polyhydroxypyridinone derivatives also form strong and stable complexes with Gd(III) that make them potentially useful as relaxation agents in magnetic resonance imaging (MRI) applications. 2 Several hydroxypyridinones, including di, tri and tetra HOPO derivatives have also been examined for their ability to achieve in vivo clearance of actinide ions. 3 Such agents may be useful for the treatment of patients exposed to actinides such as Pu(IV). The incorporation of 3-hydroxy-2-pyridinone ligands into calix [4]arenes has been shown to yield useful Th(IV) extractants. 4 Chelating resins with hydroxypyridinone ligands have been investigated for their ability to achieve the separation of actinides present in radioactive waste streams. 5 For both therapeutic and imaging applications, synthetic methods leading to poly HOPO derivatives that have the requisite water solubility and ability to form strong complexes with the target cation are needed. The most common method for the preparation of 3,2-as well as 1,2-HOPO derivatives involves the coupling of an amine with an activated carboxylic acid linker on or attached to the pyridinone ring system. 2a,6 One drawback of this approach is that the resultant HOPO derivatives usually have limited aqueous solubility due to the presence of the polyamide linkages. The direct alkylation of 2,3-dihydroxypyridine on a trimesylate has been reported to yield a tri 3,2-HOPO derivative in low yields. 7 This reaction requires harsh conditions and the highly polar product was difficult to purify. In ) and Gd(III), we desired a new method that would allow the easy incorporation of the 3,2-HOPO ligand onto a variety of platforms. The initial goal was to develop an electrophilic reagent that would allow the ready incorporation of 3,2-HOPO groups onto amines without formation of an amide linkage in the coupling step, in turn resulting in chelators with improved water solubility. In this paper, we disclose a new convenient method for the preparation of a v...
The reactions of the electrophilic iminium ester mesylate salt 1 with alcohols, phenols and thiols has been investigated. In the presence of base, thiols, phenols and thiophenol react with 1 to give the corresponding ether linked HOPO derivatives in good yields. However, the ring opening of salt 1 with alcohols could only be accomplished efficiently using a large excess of the alcohol in the presence of methanesulfonic acid at 80°C. The synthetic utility of HOPO precursor, 1, has been demonstrated by the synthesis of two polyHOPO chelators 7 and 9.Molecules containing the 3-hydroxy-2-pyridinone (3,2-HOPO) ligand have been of considerable interest because of their ability to form strong complexes with hard metal ions especially iron (III). 1 A number of HOPO chelators have been synthesized and examined for potential applications in the treatment of patients suffering from iron overload diseases. 2 Gadolinium HOPO chelates have been investigated for their use as relaxation agents in magnetic resonance imaging (MRI). 3 A number of HOPO derived chelators have been studied for their ability to achieve in vivo clearance of actinide ions such as Pu(IV). 4 Hydroxypyridinone ligands have been examined as potential extraction agents for Pu(IV) 5 and they have been attached to calix [4]arenes to yield useful Th(IV) extractants. 6 This ligand system has also been incorporated into polymers 7 , dendrimers, 8 and self-assembled monolayers on mesoporous silica. 9 Recently, a parallel synthesis of a library of metal ion chelators has incorporated HOPO ligands. 10 The most common method for the preparation of 3,2-HOPO derivatives involves the coupling of an amine or amine scaffold with an activated carboxylic acid linker attached to the pyridinone ring system. 2a, 11 This results in the formation of polyamide linkages reducing the organic and aqueous solubility of the final product. The direct alkylation of 2,3-dihydroxypyridine on a trimesylate under harsh conditions to yield a tris-3,2-HOPO derivative in low yields has been reported. 12 The alkylation of 1,7-dimethylcyclen with 3-benzyloxy-1-(2-chloroethyl)-1H-pyridin-2-one followed by hydrogenolysis has been used to prepare a diHOPO cyclen chelator. 13 In conjunction with our program to develop selective chelators 14 for actinides and trivalent cations such as Fe(III) and Gd(III), we desired a new method that would allow the easy † Portions of this work were presented at the 225th ACS National Meeting, New Orleans, LA, March 23-27, 2003 incorporation of the 3,2-HOPO ligand onto a variety of platforms. In particular, we desired a method that would allow the control of aqueous or organic solubility of the target chelator by proper choice of the scaffold and tethering methodology that avoids the traditional amide linkage. We recently disclosed the synthesis of a novel electrophilic 3,2-HOPO precursor 1, and its reactions with primary and secondary amines. 15 The reactivity of 1 was found to depend on the nature of the amine (Path A or B). 16 In general, secondary ami...
The ability to control the proliferation and cell death by inhibiting specific target kinase offers the opportunity to apply targeted therapies in the treatment of cancer. It has been found that (S)-valine-thiazole-derived compounds such as NEOS-223 are effective inhibitors of one or more of these kinases. NEOS 223 was developed, synthesized, and tested in the NCI 60 human tumor cell-screening panel demonstrating inhibition of colon (-53%), melanoma (-41%), and breast cancers (-9%). Microsomal clearance was determined in mouse, rat, dog, and human, and analyzed by LC-MS/MS by percent of parent material. IC<sub>50</sub> values for CYP inhibition of >10 μM were calculated for 1A2, 2C19, and 3A4 with IC<sub>50</sub> values of 4.86, 4.31, and 7.84 μM for 2C9 and 2D6. Microsomal clearance was high in all species with clearance rates ranging from 69-136 mL/min/kg. Plasma protein binding was determined by Rapid Equilibrium Dialysis in mice, rats, dogs, and humans. High plasma protein binding (>70%) was observed across all species. Based on the NCI results several cell lines were assayed in an MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- tetrazolium bromide) to determine cell viability in the presence of NEOS-223 resulting in <20% viability in colon, breast, melanoma, pancreatic and prostate human cancer cell lines at a 10 uM concentration. Maximum tolerated dose studies were conducted by both intraperitoneal and oral administration in mice. NEOS-223 delivered up to 80 mg/kg was well tolerated. Minimal or no toxicity was observed in acute and repeat dose animal studies. Pharmacokinetics of oral administration demonstrated adequate systemic exposure at therapeutic levels in mice, rats, and dogs. Preliminary in vivo mouse xenograft studies were performed on colon (COLO 205, HT-29 red FLUC), breast (MDA-MB-468), melanoma (M-14), pancreatic (PANC-1), and prostate (PC3) human cancer cells with significant tumor inhibition observed compared to positive control agent groups with twice daily dosing of NEOS-223. In addition, a five-day pilot oral toxicity study in rats with dose range-finding studies and a 28-day repeat dose toxicity study performed in both rats and dogs provided favorable results. NEOS-223 has demonstrated active in vitro activity along with a favorable safety profile. <i>in vivo efficacy resulted in inhibition of growth of multiple cell line. As a novel effective structure possibly targeting multiple kinases and transporters in one hybrid molecule, NEOS-223 may be a preferred monotherapy or combined therapy for multiple cancers. If upon further development, this drug is effective in humans, it would advance clinical practice and could improve current therapy significantly. Citation Format: Sumathi Chittamuru, Timothy M. Murphy, Sara A. Little, Andrew A. Taylor, Roseanne Wexler, Laxman Desai. Pre-clinical evaluation of NEOS-223, an (S)-valine-thiazole derived peptidomimetic N-heterocycle, as an anticancer agent and P-glycoprotein inhibitor [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P39.
The iminium ester mesylate salt (I) reacts as electrophile with alcohols and thiols. Reaction conditions for the synthesis of 3-hydroxy-2-pyridone derivatives are investigated. -(CHITTAMURU, S.; LAMBERT, T. N.; MARTINEZ, G.; JACOBS, H. K.; GOPALAN*, A. S.; Tetrahedron Lett. 48 (2007) 4, 567-571; Dep. Chem. Biochem., N. Mex. State Univ., Las Cruces, NM 88003, USA; Eng.) -Mais 18-135
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