In this study, a 50-membered library of substituted 4-hydroxyquinolin-2(1H)-ones and two closely related analogues was designed, scored in-silico for drug likeness and subsequently synthesized. Thirteen derivatives, all sharing a common 3-phenyl substituent showed minimal inhibitory concentratio...

The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins using NAD+ as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibito...

The reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine 1 with nucleophiles has been investigated. The different reactivity of the two chlorine atoms in 1 enabled us to obtain, by using different experimental conditions, the mono- and the di-amino-substituted derivat...

A convergent regiospecific route to the aklavinone (II) ring system is described.

An advanced intermediate in the Kishi synthesis of aklavinone was prepared. Juglone was converted into enone 4. Quinone 6 was then prepared from 4 by Michael addition and elimination of PhSOH and HCN.

The AB ring system 2 of aklavinone 1 was obtained using a chemoenzymatic protocol. Key steps are the stereoselective addition of lithium enolate of ethyl acetate to ketone 13 and the intramolecular Friedel-Crafts reaction to give tetralin 17.

Both enantiomers of compound 3, a possible intermediate for the AB ring system 2 of Aklavinone 1, were obtained in optically active form from diol 7. Key steps were the preparation of both enantiomers of monoacetate 8d, via enzymatic reactions that utilize PPL as catalyst, and the construction o...

A practical synthesis of( + )-aklavinone, the aglycone of antitumor antibiotic aclacinomycin A, is achieved by using the asymmetric aldol reaction of 6a to 10a as the key step.

A formal synthesis of the AB-ring of aklavinone 3 was achieved via the asymmetric synthesis of diol 8 prepared in three steps from tetralone 5. The crucial step involved the asymmetric hydroxylation of 5 in ≥ 95% ee using (camphorylsulfonyl)oxaziridine derivative (+)-4b.

A stereospecific synthesis of aklavinone (2) in 16 steps from 5-methoxy- 1-tetralone with an overall yield of 6.5% is described. Regiospecific control in forming the BCD-ring chromophore was accomplished by coupling of a preformed bicyclic AB-ring aldehyde (29) with a nucleophilic D-ring carboxa...

The rdm genes B, C and E from Streptomyces purpurascens encode enzymes that tailor aklavinone and aclacinomycins. We report that in addition to hydroxylation of aklavinone to ϵ-rhodomycinone, RdmE (aklavinone-11-hydroxylase) hydroxylated 11-deoxy-β-rhodomycinone to β-rhodomycinone both in vivo...

In the biosynthesis of several anthracyclines, aromatic polyketides produced by many Streptomyces species, the aglycone core is modified by a specific flavin adenine dinucleotide (FAD)- and NAD(P)H-dependent aklavinone-11-hydroxylase. Here, we report the crystal structure of a ternary complex of...

Aklavinone-11-hydroxylase (RdmE) is a FAD monooxygenase participating in the biosynthesis of daunorubicin, doxorubicin and rhodomycins. The rdmE gene encodes an enzyme of 535 amino acids. The sequence of the Streptomyces purpurascens enzyme is similar to other Streptomyces aromatic polyketide hy...

The in vitro evaluation of thieno[3,2-d]pyrimidines identified halogenated compounds 1 and 2 with antiproliferative activity against three different cancer cell lines. A structure activity relationship study indicated the necessity of the chlorine at the C4-position for biological activity. The ...

A series of 4-morpholino-2-phenylquinazolines and related derivatives were prepared and evaluated as inhibitors of PI3 kinase p110α. In this series, the thieno[3,2-d]pyrimidine derivative 15e showed the strongest inhibitory activity against p110α, with an IC50 value of 2.0 nM, and inhibited pr...

Motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines a series of 24 new 2-substitutedhexahydrocycloocta[4,5] thieno[2,3-d]pyrimidines with different substituents at C-4 position and hexahydrocycloocta[4,5]thieno[3,2-e]-1,2,4-triazolo[4,3-c]pyrimidines were synthesized...

A series of thieno[3,2-d]pyrimidines bearing a hydroxamic acid moiety as novel HDAC inhibitors were designed and synthesized. The structures of the new synthesized compounds were confirmed using IR, 1H, 13C NMR spectrum. Compounds 11–13 showed potent inhibitory activities against HDACs with IC5...

Four series of novel thieno[3,2-d]pyrimidine and quinazoline derivatives containing N-acylhydrazone or semicarbazone were designed, synthesized, and evaluated for their biological activity. Of which compound 14 showed the most potent antitumor activities with IC50 values of 1.78 μM, 1.02 μM, 1...

Stereochemistry of 3t,5t-Dimethyl-N-nitroso-2r,6c-bis(o-chlorophenyl) piperidin-4-one oxime (1) and 3t,5t-Dimethyl-N-nitroso-2r,6c-bis(p-chlorophenyl) piperidin-4-one oxime (2) has been studied using 1H, 13C and two-dimensional NMR spectra. Analysis of the spectral data shows that both the compo...

A series of novel indole-2-carboxylate derivatives were synthesized and assayed to determine their in vitro broad-spectrum antiviral activities. The biological results showed that some of the synthesized compounds exhibited potent broad-spectrum antiviral activity. Notably, compound 8f showed th...