Hea Ok Kim

Fluorocyclopentenyl-cytosine with broad spectrum and potent antitumor activity.

On the basis of the potent biological activity of cyclopentenyl-pyrimidines, fluorocyclopentenyl-pyrimidines were designed and synthesized from D-ribose. Among these, the cytosine derivative 5a showed highly potent antigrowth effects in a broad range of tumor cell lines and very potent antitumor activity in a nude mouse tumor xenograft model implanted with A549 human lung cancer cells. However, its 2-deoxycytidine derivative 5b did not show any antigrowth effects, indicating that 2-hydroxyl group is essential for the biological activity.

The antitumor effect of LJ-529, a novel agonist to A3 adenosine receptor, in both estrogen receptor–positive and estrogen receptor–negative human breast cancers

Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) α status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c–poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27kip was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types. [Mol Cancer Ther 2006;5(3):685–92]

Discovery of a new template for anticancer agents: 2'-deoxy-2'-fluoro-4'-selenoarabinofuranosyl-cytosine (2'-F-4'-seleno-ara-C).

The first synthesis of 2-deoxy-2-fluoro-4-selenoarabinofuranosyl pyrimidines as potent anticancer agents was accomplished using the DAST fluorination as a key step. It was first revealed that selenium atom participated in the DAST fluorination of 4-selenonucleosides and that conformational bias induced by bulky selenium acted as a decisive factor in the DAST fluorination. Among compounds tested, 2-F-4-seleno-ara-C (4a) exhibited highly potent anticancer activity in all cancer cell lines tested and was more potent than ara-C (1).

Structure-Activity Relationships of Truncated D-and L-4'-Thioadenosine Derivatives as Species-Independent A3 Adenosine Receptor Antagonists

Novel D- and l-4-thioadenosine derivatives lacking the 4-hydroxymethyl moiety were synthesized, starting from d-mannose and d-gulonic gamma-lactone, respectively, as potent and selective species-independent A 3 adenosine receptor (AR) antagonists. Among the novel 4-truncated 2-H nucleosides tested, a N(6)-(3-chlorobenzyl) derivative 7c was the most potent at the human A 3 AR (K i = 1.5 nM), but a N(6)-(3-bromobenzyl) derivative 7d showed the optimal species-independent binding affinity.

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A2A and A3 Adenosine Receptor Ligands

Truncated N(6)-substituted-4-oxo- and 4-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.

A New DNA Building Block, 4′-Selenothymidine: Synthesis and Modification to 4′-Seleno-AZT as a Potential Anti-HIV Agent

The first synthesis of 4-selenothymidine (1), a novel DNA building block, and 4-seleno-AZT (2) was accomplished from 2-deoxy-d-ribose via stereoselective formation of 2-deoxy-4-seleno-d-furanose 17 and a Pummerer-type base condensation as key steps. 4-Selenothymidine (1) was discovered to adopt the same 2-endo/3-exo conformation as thymidine, which is unusual in that 4-selenouridine has the opposite conformation to that of uridine.

Stereoselective Synthesis of MLN4924, an Inhibitor of NEDD8-Activating Enzyme

MLN4924 (1), which is in clinical trials as an anticancer agent, was stereoselectively synthesized from d-ribose via a route involving stereoselective reduction, regioselective cleavage of an isopropylidene moiety, and selective displacement of a cyclic sulfate moiety as key steps.

Stereoselective synthesis and conformational study of novel 2',3'-Didehydro-2',3'-dideoxy-4'-selenonucleosides.

Stereoselective synthesis of novel 2,3-didehydro-2,3-dideoxy-4-selenonucleosides (4-seleno-d4Ns) 4a- c was accomplished via 4-selenoribofuranosyl pyrimidines 11a- c, as key intermediates. 4-Selenoribofuranosyl pyrimidines 11a- c were efficiently synthesized from d-ribose or d-gulonic gamma-lactone using a Pummerer-type condensation as a key step. Introduction of 2,3-double bond was achieved by treating cyclic 2,3-thiocarbonate with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine.

Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2-Hexynyl-N6-Substituted-(N)-Methanocarba-nucleosides as A3 Adenosine Receptor Antagonists and Partial Agonists

Truncated N6-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4′-thioadenosines. Hydrophobic N6 and/or C2 substituents were tolerated in A3AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA2AAR affinity. A small hydrophobic alkyl (4b and 4c) or N6-cycloalkyl group (4d) showed excellent binding affinity at the hA3AR and was better than an unsubstituted free amino group (4a). A3AR affinities of 3-halobenzylamine derivatives 4f–4i did not differ significantly, with Ki values of 7.8–16.0 nM. N6-Methyl derivative 4b (Ki = 4.9 nM) was a highly selective, low efficacy partial A3AR agonist. All compounds were screened for renoprotective effects in human TGF-β1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-β1-induced collagen I upregulation, and their A3AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 μM), indicating its potential as a good therapeutic candidate for treating renal fibrosis.

Activation and Desensitization of Rat A3-Adenosine Receptors by Selective Adenosine Derivatives and Xanthine-7-Ribosides

Xanthine and adenosine derivatives, known to bind to recombinant rat A3 adenosine receptors stably expressed in Chinese hamster ovary cells, were characterized in a functional assay consisting of activation of A3 receptor‐stimulated binding of [35S]GTPγS in rat RBL‐2H3 cell membranes. 1,3‐Dibutylxanthine‐7‐riboside‐5′‐N‐methylcarboxamide (DBXRM, 7b), previously shown to inhibit adenylyl cyclase via rat A3 receptors with full efficacy, appeared to be a partial agonist at the rat A3 receptor of RBL‐2H3 cells. Full agonists, such as Cl‐IB‐MECA or I‐AB‐MECA, were more potent and effective than the partial agonist DBXRM in causing desensitization of rat A3 receptors, as indicated by loss of [35S]GTPγS binding. At A1 receptors, antagonism of agonist‐elicited inhibition of rat adipocyte adenylyl cyclase was observed for several xanthine‐7‐riboside derivatives that had been shown to be full agonists at rat A3 receptors. A new xanthine riboside (3′‐deoxyDBXRM, 7c) was synthesized and found to be a partial agonist at rat A3 receptors and an antagonist at rat A1 receptors. Thus, it is possible for the same compound to stimulate one adenosine receptor subtype (A3) and block another subtype (A1) within the same species. Drug Dev. Res. 44:97–105, 1998.