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1.
Figure 1

Figure 1. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Structures of flavopiridol and representative flavopiridol analogues.

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
2.
3.
Figure 2

Figure 2. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Key H-bonding interactions between CDK2 and dechloroflavopiridol (). SAR relationship for flavopiridol and targeted compounds ().

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
4.
Figure 4

Figure 4. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Docked conformations in the CDK2 receptor for flavopiridol (1, ) and flavopiridol analogue 19b ().

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
5.
Scheme 3

Scheme 3. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Parallel synthesis was employed to react various benzoyl chlorides with 8-aminoflavone 10 using Hünig's base to generate 8-amidoflavones 17ae ().

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
6.
Scheme 5

Scheme 5. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Heterocyclic analogues at C8 were prepared using various alkyl dibromides, which were reacted with 8-aminoflavone 10 under basic conditions to afford the corresponding C8-pyrrolidinyl flavopiridol analogue 20a, C8-piperidinylflavopiridol analogue 20b, and C8-morpholinylflavopiridol analogue 20c ().

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
7.
Scheme 7

Scheme 7. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

The sulfonamido flavones 24a–c were prepared by treating 8-aminoflavone 10 with a variety of sulfonyl chlorides under basic conditions to yield products 24 in moderate yields ().

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
8.
Scheme 4

Scheme 4. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Acylation of 16 furnished N,O-bis-acylated products 18, which were hydrolyzed with KOH to obtain N-acylated products 19 (). The structure of 18b (R = Cl), as well as the assignment of regioisomers 15a and 15b, were confirmed by X-ray crystallography of 18b (R = Cl).

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
9.
Scheme 6

Scheme 6. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Reactions between N-Boc-protected amino acids and 8-aminoflavone 10 were carried out using 4-methyl morpholine (NMM) as base in THF with sec-butyl chloroformate activation (formation of the mixed anhydride) to yield amides 21ad and 22ad (). 8-Aminoflavone 10 also reacted with sec-butyl chloroformate itself to give by-product 23 in less than 10% yield.

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
10.
Scheme 2

Scheme 2. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Accordingly, we initially designed a key 8-aminoflavone intermediate (), which was designed to retain the hydrogen bonding interactions with Glu81, Leu83, possibly also Wat327 (), and the interactions of the 2-(2-chlorophenyl) group of 1 with the protein, avoiding the "frequent-hitters" pharmacophore. The 8-amino group provides a new site for introduction of various hydrogen bond donor/acceptor motifs aimed at providing additional interactions with the ATP binding pocket and surrounding areas so as to potentially impart potency and selectivity. Guided by the aforementioned SAR studies, we initiated the synthesis of four classes of 8-amino-modified flavones related to flavopiridol (). The synthesis of the key 8-aminoflavone intermediates 10 and 16 are outlined in and , respectively.

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.
11.
Scheme 1

Scheme 1. From: Design, Synthesis, Antiproliferative and CDK2-Cyclin A Inhibitory Activity of Novel Flavopiridol Analogues.

Accordingly, we initially designed a key 8-aminoflavone intermediate (), which was designed to retain the hydrogen bonding interactions with Glu81, Leu83, possibly also Wat327 (), and the interactions of the 2-(2-chlorophenyl) group of 1 with the protein, avoiding the "frequent-hitters" pharmacophore. The 8-amino group provides a new site for introduction of various hydrogen bond donor/acceptor motifs aimed at providing additional interactions with the ATP binding pocket and surrounding areas so as to potentially impart potency and selectivity. Guided by the aforementioned SAR studies, we initiated the synthesis of four classes of 8-amino-modified flavones related to flavopiridol (). The synthesis of the key 8-aminoflavone intermediates 10 and 16 are outlined in and , respectively.

Yu Mi Ahn, et al. Bioorg Med Chem. ;15(2):702-713.

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