Ho H. Lee

University of Auckland, Окленд, Auckland, New Zealand

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Publications (27)93.51 Total impact

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    ABSTRACT: Racemic 2-{[1-(chloromethyl)-5-nitro-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}aminoethyl dihydrogen phosphate, a synthetic nitro derivative of the duocarmycins, is a hypoxia-selective prodrug active against radiation-resistant tumour cells at nontoxic doses in mice. An intermediate in the synthesis of this prodrug was resolved by chiral HPLC and the absolute configuration assigned by X-ray crystallography. The intermediate was used to prepare the prodrug's enantiomers, and also the enantiomers of the active nitro and amino metabolites. In vitro analysis in the human cervical carcinoma cell line SiHa showed that both nitro enantiomers are hypoxia-selective cytotoxins, but the "natural" S enantiomer is at least 20-fold more potent. Examination of extracellular amino metabolite concentrations demonstrated no enantioselectivity in the hypoxia-selective reduction of nitro to amino. Low levels of amino derivative were also found in aerobic cell suspensions, sufficient to account for the observed oxic toxicity of the nitro form. At an equimolar dose in SiHa-tumour bearing animals, the (-)-R enantiomer of the prodrug was inactive, while the (+)-S enantiomer caused significantly more hypoxic tumour cell kill than the racemate. At this dose, the combination of (+)-S-prodrug and radiation eliminated detectable colony-forming cells in four out of five treated tumour-bearing animals.
    ChemMedChem 10/2011; 6(10):1860-71. DOI:10.1002/cmdc.201100271 · 3.05 Impact Factor
  • Cancer Research 01/2011; 70(8 Supplement):LB-297-LB-297. DOI:10.1158/1538-7445.AM10-LB-297 · 9.28 Impact Factor
  • Ho H. Lee · William A. Denny
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 31(3). DOI:10.1002/chin.200003106
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    ABSTRACT: A series of novel tricyclic triazine-di- N-oxides (TTOs) related to tirapazamine have been designed and prepared. A wide range of structural arrangements with cycloalkyl, oxygen-, and nitrogen-containing saturated rings fused to the triazine core, coupled with various side chains linked to either hemisphere, resulted in TTO analogues that displayed hypoxia-selective cytotoxicity in vitro. Optimal rates of hypoxic metabolism and tissue diffusion coefficients were achieved with fused cycloalkyl rings in combination with both the 3-aminoalkyl or 3-alkyl substituents linked to weakly basic soluble amines. The selection was further refined using pharmacokinetic/pharmacodynamic model predictions of the in vivo hypoxic potency (AUC req) and selectivity (HCD) with 12 TTO analogues predicted to be active in vivo, subject to the achievement of adequate plasma pharmacokinetics.
    Journal of Medicinal Chemistry 11/2008; 51(21):6853-65. DOI:10.1021/jm800967h · 5.48 Impact Factor
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    ABSTRACT: A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057 microM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.
    European Journal of Medicinal Chemistry 07/2008; 43(6):1276-96. DOI:10.1016/j.ejmech.2007.07.016 · 3.43 Impact Factor
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    ABSTRACT: Pyrrolo[3,4-c]carbazoles bearing solubilising basic side chains at the 8-position retain potent Wee1 and Chk1 inhibitory properties in isolated enzyme assays, and evidence of G2/M checkpoint abrogation in several cellular assays. Co-crystal structure studies confirm that the primary binding to the Wee1 enzyme is as described previously, with the C-8 side chains residing in an area of bulk tolerance.
    Bioorganic & medicinal chemistry letters 03/2008; 18(3):929-33. DOI:10.1016/j.bmcl.2007.12.046 · 2.33 Impact Factor
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    ABSTRACT: High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.
    Journal of Medicinal Chemistry 09/2006; 49(16):4896-911. DOI:10.1021/jm0512591 · 5.48 Impact Factor
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    ABSTRACT: Nitrobenzyl quaternary salts of nitrogen mustards have been previously reported as hypoxia-selective cytotoxins. In this paper we describe the synthesis and evaluation of a series of heterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosen to cover a range of one-electron reduction potentials (from -277 to -511 mV) and substitution patterns. All quaternary salt compounds were less toxic in vitro than mechlorethamine, and all were more toxic under hypoxic than aerobic conditions, although the differentials were highly variable within the series. The most promising analogue, imidazole 2, demonstrated DNA cross-linking selectively in hypoxic RIF-1 cells, and was active in vivo in combination with radiation or cisplatin. However, 2 also produced unpredictable toxicity in vivo, suggestive of nonspecific nitrogen mustard release, and this has restricted further development of these compounds as hypoxia-selective cytotoxins.
    Journal of Medicinal Chemistry 11/2001; 44(21):3511-22. DOI:10.1021/jm010202l · 5.48 Impact Factor
  • Ho H. Lee · William A. Denny
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    ABSTRACT: A large-scale synthesis of the bis-bioreductive drug 1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione bis-N-oxide (AQ4N) has been developed. This six-step synthesis provides AQ4N in 20% overall yield from readily available tetrachlorophthalic anhydride. The key step was a KF–NaF-mediated conversion of 3,6-dichlorophthalic anhydride to 3,6-difluorophthalic anhydride, which could be achieved in 77% yield on a 100 g scale. A trace impurity in AQ4N was determined (by LC-MS and independent synthesis) to be the mono-N-oxide 1-amino-4-[2-(dimethylamino)ethyl]amino-5,8-dihydroxyanthracene-9,10-dione N-oxide. This is formed spontaneously from AQ4N under a number of conditions, including during HPLC on reversed-phase columns.
    Journal of the Chemical Society Perkin Transactions 1 10/1999; DOI:10.1039/a905611d · 1.95 Impact Factor
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    ABSTRACT: A series of nuclear-substituted derivatives of nitracrine N-oxide (2; a bis-bioreductive hypoxia-selective cytotoxin) were prepared and evaluated, seeking analogues of lower nitroacridine reduction potential. Disubstitution with Me or OMe groups at the 4- and 5-positions did not provide analogues with one-electron reduction potentials significantly lower than those of the corresponding monosubstituted derivatives (E(1) ca. -350 mV for both the 4-OMe and 4,5-diOMe compounds). This appears not to be due to a concomitant raising of the acridine pKa but to a lack of direct electronic effect of substituents in the ring not bearing the nitro group. Conversely, placing two OMe groups in the nitro-bearing ring does result in a substantial further lowering of reduction potential (the 2,4-diOMe analogue has an E(1) of -401 mV). The mono- and disubstituted N-oxides have substantially lower cytotoxicities than the parent nitracrine N-oxide 2 but generally retain very high hypoxic selectivity. The OMe-substituted N-oxides all showed greater metabolic stability than 2 in hypoxic AA8 cell cultures, and the 4-OMe compound 6 had improved activity in EMT6 multicellular spheroids suggesting that this metabolic stabilization may allow more efficient diffusion in tumor tissue. The parent compound 2 was selectively toxic to hypoxic cells in KHT tumors in vivo and clearly superior to nitracrine itself (although only at doses which would eventually be lethal to the host). The analogues of lower E(1), including 6, were not superior to 2 in vivo, indicating that metabolic stabilization of the nitro group is not alone sufficient to improve therapeutic utility.
    Journal of Medicinal Chemistry 07/1996; 39(13):2508-17. DOI:10.1021/jm9600104 · 5.48 Impact Factor
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    ABSTRACT: While reaction of 2-bromo-5-nitrothiazole (2) with weakly basic secondary aliphatic amines gives the expected 2-amino products from nucleophilic displacement of the bromine, reaction of the isomeric 5-bromo-2-nitrothiazole (3) with such amines gives mixtures of the expected 5-amino products together with 2-aminated 5-nitrothiazole rearrangement products. The identity of the latter were detemined by alternative synthesis, and by X-ray crystallographic determination of a derivative. The mechanism proposed is a slow thermal isomerization of 5-bromo-2-nitrothiazole (3) to the much more reactive 2-bromo-5-nitro isomer 2 which competes, in the case of relatively weak amine nucleophiles, with the direct (but slow) nucleophilic displacement of the 5-bromo group to form the normal displacement products.
    Journal of Heterocyclic Chemistry 07/1996; 33(4):1191-1194. DOI:10.1002/jhet.5570330431 · 0.87 Impact Factor
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    ABSTRACT: A series of analogues of the previously described compound N-[2-(2-methyl-5-nitroimidazol-1H-yl)ethyl]-4-(2-nitroimidazol- 1H-yl)butanamide (4), a novel hypoxic cell cytotoxin and radiosensitizer, have been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitization in vitro. The new derivatives were designed to overcome the low aqueous solubility of 4 and its slow kinetics of killing under hypoxia. The nitroheterocycle unit had a significant effect on solubility, with 3-nitrotriazoles being about 6-fold more soluble than the corresponding 2-nitroimidazoles. Analogues with a range of neutral linker chains (polyhydroxy, alkanesulfonamide, and bisamide) showed only slightly improved solubility and were unable to be fully evaluated. However, a series of analogues with cationic amine linkers had adequate aqueous solubility (up to 280 mM). The amine analogues could not be prepared by direct reduction of precursor amides such as 4 and were most conveniently synthesized by aza-Wittig condensation of the appropriate azide and aldehyde components. The amine-linked compounds were more cytotoxic than 4, with the symmetrical bis(2-nitroimidazole) derivatives (13 and 14) up to 9-fold more potent. They showed hypoxic selectivities comparable to that of 4 (ca. 200-fold) but had much more rapid kinetics of killing under hypoxia, resulting in high hypoxic selectivity at early times in culture. The nature of the mechanism of cytotoxicity of these compounds remains unclear but appears not to be DNA cross-linking, with the compounds showing a lack of hypersensitivity toward repair-deficient UV4 cells. The enhanced solubility and hypoxia-selective cytotoxicity (at early times) of 13 compared with 4 represent significant potential advantages.
    Journal of Medicinal Chemistry 06/1995; 38(11):1928-41. DOI:10.1021/jm00011a013 · 5.48 Impact Factor
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    ABSTRACT: A series of 3-nitro-4-alkylbenzamides has been prepared, and the effects of nitro group torsion angle on reduction potential studied. Nitro and carboxamide group torsion angles have been determined by 17O NMR spectroscopy and X-ray crystallography, and one-electron reduction potentials by pulse radiolysis. 17O Chemical shifts indicated similar amide torsion angles (from 35° to 45°) as the alkyl group varied from hydrogen to tert-butyl, but widely differing nitro group torsion angles; from 36°(hydrogen) to 92°(tert-butyl). Crystal structures of the isopropyl and tert-butyl derivatives indicate amide group torsion angles (50° and 64°) somewhat larger than those predicted by 17O NMR, and nitro group torsion angles (59° and 65° respectively) considerably smaller than those predicted by 17O NMR (75° and 92° respectively). These results support earlier data that 17O chemical shifts predict for erroneously large nitro group torsion angles in non-rigid but sterically crowded molecules, because of additional contributions to the shift from van der Waals repulsions. The drop in reduction potential of 90 mV between the unsubstituted and tert-butyl derivatives is too large to be accounted for by the electronic effects of the alkyl groups, and indicates that increasing the nitro group torsion angle significantly lowers reduction potential.
    Journal of the Chemical Society Perkin Transactions 2 02/1994; DOI:10.1039/p29940000291
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    ABSTRACT: The sequence specificity of DNA damage caused by cis-diamminedichloroplatinum(II) (cisplatin) and four analogues in human (HeLa) cells was studied using Taq DNA polymerase and a linear amplification system. The primer extension is inhibited by the drug-DNA adducts, and hence the sites of these lesions can be analyzed on DNA sequencing gels. The repetitive alphoid DNA was used as the target DNA in human cells. A comparison was made between adduct formation in human cells and in purified DNA. The sequence-specific position and relative intensity of damage was similar in both systems for cisplatin, dichloro(ethylenediammine)platinum(II) (PtenCl2), and N-[3-N-(ethylenediamino)propyl]acridine-4-carboxamidedichloropl atinum(II) (4AcC3PtenCl2). However, no DNA damage could be detected in cells for trans-diamminedichloroplatinum(II) (transPt) or N-[3-N-(ethylenediamino)propyl]acridine-2-carboxamide-dichloroplat inum(II) (2AcC3PtenCl2) despite the ability of these latter analogues to damage purified DNA. Cisplatin, PtenCl2, and 4AcC3PtenCl2, which significantly damaged DNA inside cells, also show antitumor activity in mouse models. However, transPt and 2AcC3PtenCl2, which did not detectably damage DNA inside cells, did not show such antitumor activity. This correlation between intracellular DNA damaging ability and in vivo antitumor activity indicates the potential use of the human cells/Taq DNA polymerase/linear amplification technique as a convenient method for screening new cisplatin analogues for useful chemotherapeutic activity.
    Biochemistry 01/1993; 31(47):11812-7. DOI:10.1021/bi00162a020 · 3.01 Impact Factor
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    ABSTRACT: A series of acridine-2- and -4-carboxamide-linked analogues of PtenCl2 has been prepared and evaluated for biological activity against several tumor cell lines in vitro and in vivo. The platinum complexes were generally more cytotoxic than the corresponding ligands against wild-type P388 leukemia cells in vitro, with acridine-4-carboxamide complexes being the more effective. In contrast to cisplatin and PtenCl2, the complexes were equally active in vitro against both wild-type and cisplatin-resistant P388 lines. The 4-carboxamide complexes showed high levels of in vivo activity (ILS greater than 100%) against wild-type P388 using a single-dose protocol, and one compound was also significantly active in vivo in a cisplatin-resistant line, against which cisplatin and PtenCl2 are inactive.
    Journal of Medicinal Chemistry 09/1992; 35(16):2983-7. DOI:10.1021/jm00094a008 · 5.48 Impact Factor
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    ABSTRACT: A series of substituted dibenzo[1,4]dioxin-1-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. The required substituted dibenzo[1,4]dioxin-1-carboxylic acids were prepared by a variety of methods. No regiospecific syntheses were available for many of these, and separation of the mixtures of regioisomers obtained was sometimes difficult. The dibenzo[1,4]dioxin-1-carboxamides are active against wild-type P388 leukemia in vitro and in vivo, with structure-activity relationships resembling those for both the acridine-4-carboxamide and phenazine-1-carboxamide series of DNA-intercalating antitumor agents. In all three series, substituents placed peri to the carboxamide sidechain (the 5-position in the acridines, and the 9-position in the phenazines and dibenzo[1,4]dioxins) enhance activity and potency. The 9-chlorodibenzodioxin-1-carboxamide was also curative against the remotely sited Lewis lung carcinoma. Several of the compounds showed much lower levels of cross-resistance to the P388/AMSA line than classical DNA-intercalating agents, which suggests that their primary mechanism of action may not be via interference with topoisomerase II alpha. This is of interest with regard to the development of drugs to combat resistance mechanisms which arise by the expression of the topo II beta isozyme.
    Journal of Medicinal Chemistry 02/1992; 35(2):258-66. DOI:10.1021/jm00080a009 · 5.48 Impact Factor
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    ABSTRACT: Two different classes of cis-diaminedichloroplatinum(II) complexes linked to the DNA-intercalating chromophore 9-anilinoacridine have been synthesized and evaluated as DNA-targeted antitumor agents. Two different Pt chelating ligands were investigated (based on 1,2-ethanediamine and 1,3-propanediamine), designed to deliver the Pt in an orientation likely to respectively enhance either intrastrand or interstrand cross-linking. Although both sets of ligands were somewhat unstable under neutral or basic conditions with respect to disproportionation, the corresponding Pt complexes, once prepared, appeared to be quite stable. All the Pt complexes were monitored for purity by TLC, HPLC, and FAB mass spectra, and the mode of Pt coordination was established by 195Pt NMR spectroscopy. The complexes appeared to cause simultaneous platination and intercalative unwinding of plasmid DNA. In vitro studies were carried out with both wild-type and cisplatin-resistant P388 cell lines. Whereas cisplatin itself and the ethylenediamine and 1,3-propanediamine complexes used as standards were about 10-fold less active against the resistant line, the ethylenediamine-linked Pt complexes showed no differential toxicity between the two lines and the propanediamine-linked complexes showed significant differentials (up to 8-fold) in favor of the cisplatin-resistant line. However, these were no greater than those shown by the unplatinated ligands themselves. The majority of the acridine complexes were inactive in vivo against the wild-type P388 leukemia. They were very insoluble, and although a suitable formulation was found, this may have been a factor. It is also possible that these compounds bind in such a way as to direct the Pt away from the major groove.
    Journal of Medicinal Chemistry 12/1990; 33(11):3008-14. DOI:10.1021/jm00173a015 · 5.48 Impact Factor
  • Ho H. Lee · William A. Denny
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    ABSTRACT: An improved general synthesis of substituted dibenzo[1,4]dioxines by reaction of catechol and substituted 1,2-dichloro- or 2-chloronitro-benzenes with metallic potassium in hexamethylphosphoramide is reported. The yields are generally superior to those in published methods, and in particular the reaction appears the one of choice for the synthesis of both the parent dibenzodioxine and the 1-carboxy derivative.
    Journal of the Chemical Society Perkin Transactions 1 01/1990; DOI:10.1039/p19900001071 · 1.95 Impact Factor
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    ABSTRACT: The synthesis of the masked aminopyrazolecarboxylic acid synthons (11a,b and 12a,b) from pyrazole-3,5-dicarboxylic acid (6) and the determination of their structures by X-ray crystallography are detailed. The compounds are useful for the synthesis of polypyrazolecarboxamides analogous to the DNA minor groove binding antibiotics distamycin A and netropsin.
    The Journal of Organic Chemistry 01/1989; 54(2). DOI:10.1021/jo00263a032 · 4.64 Impact Factor
  • The Journal of Organic Chemistry 12/1988; 53(26). DOI:10.1021/jo00261a010 · 4.64 Impact Factor

Publication Stats

432 Citations
93.51 Total Impact Points

Institutions

  • 1976–2011
    • University of Auckland
      • • Auckland Cancer Society Research Centre
      • • Faculty of Medical and Health Sciences
      • • School of Medical Sciences
      • • Department of Medicine
      • • School of Chemical Sciences
      Окленд, Auckland, New Zealand