Synthetic studies on altohyrtins (spongistatins): synthesis of the C29–C44 (EF) portion

Novel N1-substituted thymine derivatives related to 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine have been synthesized and evaluated against thymidine kinase-2 (TK-2) and related nucleoside kinases [i.e., Drosophila melanogaster deoxynucleoside kinase (Dm-dNK) and herpes simplex virus type 1 thymidine kinase (HSV-1 TK)]. The thymine base has been tethered to a distal triphenylmethoxy moiety through a polymethylene chain (n = 3-8) or through a (2-ethoxy)ethyl spacer. Moreover, substitutions at position 4 of one of the phenyl rings of the triphenylmethoxy moiety have been performed. Compounds with a hexamethylene spacer (18, 26b, 31) displayed the highest inhibitory values against TK-2 (IC50 = 0.3-0.5 microM). Compound 26b competitively inhibited TK-2 with respect to thymidine and uncompetitively with respect to ATP. A rationale for the biological data was provided by docking some representative inhibitors into a homology-based model of human TK-2. Moreover, two of the most potent TK-2 inhibitors (18 and 26b) that also inhibit HSV-1 TK were able to reverse the cytostatic activity of 1-(beta-D-arabinofuranosyl)thymine (Ara-T) and ganciclovir in HSV-1 TK-expressing OST-TK-/HSV-1 TK+ cell cultures.

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“…1 H NMR was identical to that described. 3,4 6-(Triphenylmethoxy)hexanol (12). Prepared from 1,6-hexanediol (6).…”

mentioning

confidence: 99%

N-Substituted Thymine Derivatives as Mitochondrial Thymidine Kinase (TK-2) Inhibitors

et al. 2006

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“…Even if this strategy allowed assembly of the two spiroketals' subunits, further elaboration into the natural C (14)eC (17) fragment could only be achieved in low yields. Nakata and co-workers also developed a synthetic route toward the EF rings' subunit [34] making use of a coupling between a C(29)eC(37) vinyl bromide to an F-ring C(38) Weinreb amide (Fig. 34).…”

Section: Synthetic Approaches Toward Key Subunits Of Spongistatins/almentioning

confidence: 99%

Spongistatins: Biological activity and synthetic studies

Gerber‐Lemaire

Vogel

2008

Comptes Rendus. Chimie

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“…Two approaches to the F ring of spongistatin 1 have been reported recently, the former making use of an enol ether precursor via epoxidation and ring opening, 158 while the latter uses the ring-opening of a known bicyclic acetal to prepare this portion. 159 A further total synthesis of spongistatin 1, making extensive use of aldol chemistry, features the cyclisation step shown in Scheme 70. Initially a 1 : 1 mixture of epimers was formed, but treatment with base gave clean equilibration to the stereoisomer shown.…”

Section: Six Membered Ringsmentioning

confidence: 99%