Arcyriaflavin A

IC50: 0.2 μM for HCMV [1], 0.14 μM for D1–CDK4 [2]

The natural product Arcyriaflavin A, unsubstituted indolocarbazole, was a potent selective inhibitor of human cytomegalovirus (HCMV) replication. HCMV infection is typically unnoticed in healthy people, but can be life-threatening for the immunocompromised.

In vitro: Arcyriaflavin A is a potent, selective inhibitor of HCMV replication in cell culture, and the anti-HCMV activity appeared no relation to the inhibition of protein kinase C. The imide NH was identified to be essential for anti-HCMV activity [1]. Arcyriaflavin A also has been showed the inhibitory activity against D1/CDK4 with a IC50 of 59 nM. Based on X-ray co-crystal structure of staurosporine and the human CDK2, the acidic proton of the maleimide moiety and the carbonyl group play critical roles by acting as a hydrogen bond donor and acceptor in the ATP binding pocket of CDK2 [2].

In vivo: So far, no in vivo study has been conducted.

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Slater MJ, Cockerill S, Baxter R, Bonser RW, Gohil K, Gowrie C, Robinson JE, Littler E, Parry N, Randall R, Snowden W.  Indolocarbazoles: potent, selective inhibitors of human cytomegalovirus replication. Bioorg Med Chem. 1999 Jun;7(6):1067-74.
[2] Zhu G, Conner S, Zhou X, Shih C, Brooks HB, Considine E, Dempsey JA, Ogg C, Patel B, Schultz RM, Spencer CD, Teicher B, Watkins SA.  Synthesis of quinolinyl/isoquinolinyl[a]pyrrolo [3,4-c] carbazoles as cyclin D1/CDK4 inhibitors. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1231-5.

Arcyriaflavin A monohydrate.[Pubmed:21285502]

Acta Crystallogr C. 2011 Feb;67(Pt 2):o57-9.

The asymmetric unit of the title compound comprises the monohydrated form of the natural product Arcyriaflavin A [systematic name: 12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione monohydrate], C(20)H(11)N(3)O(2).H(2)O. Individual molecular units are engaged in hydrogen-bonding interactions, forming two-dimensional zigzag supramolecular layers parallel to the (102) plane. The close packing of the layers is mediated by strong co-operative pi-pi stacking interactions, in tandem with interlayer hydrogen bonds involving the solvent water molecule.

Open analogues of arcyriaflavin A. Synthesis through Diels-Alder reaction between maleimides and 1-aryl-3-tert-butyldimethylsiloxy-1, 3-butadienes.[Pubmed:10843621]

J Org Chem. 2000 Jun 2;65(11):3387-94.

The preparation of a range of open analogues of Arcyriaflavin A is described. The synthetic approach is based on the use of perhydroisoindole-1,3,5-triones as key intermediates, which were obtained via Diels-Alder methodology using 1-aryl-3-siloxy-1, 3-butadienes as starting materials. Fischer indolization and aromatization processes afforded different methoxy-substituted arylpyrrolocarbazoles. The stereochemistry and conformation of the Diels-Alder products and the regiochemistry of the indolization reactions are supported by NMR and molecular modeling studies.

Homoarcyriaflavin: Synthesis of Ring-Expanded Arcyriaflavin Analogues.[Pubmed:11674727]

J Org Chem. 1999 Oct 29;64(22):8130-8137.

The construction of the ring-expanded carbazole system, forming arcyriaflavin homologues, is efficiently accomplished by the reaction of 2,2'-bridged bis-indoles with 3,4-dibromo-2,5-dihydro-1H-2,5-pyrroledione derivatives under Grignard conditions. A ring size of up to nine members in the central ring is achievable. Substitutions either at the indole system or at the imide-N are also possible. The conformation of homoarcyriaflavins as a cross-link between the rigid arcyriaflavins and the flexible arcyriarubins was investigated by NMR, X-ray, and semiempiric quantum chemical calculation methods.

Aryl[a]pyrrolo[3,4-c]carbazoles as selective cyclin D1-CDK4 inhibitors.[Pubmed:14552791]

Bioorg Med Chem Lett. 2003 Nov 3;13(21):3835-9.

The synthesis of new analogues of Arcyriaflavin A in which one indole ring is replaced by an aryl or heteroaryl ring is described. These new series of aryl[a]pyrrolo[3,4-c]carbazoles were evaluated as inhibitors of Cyclin D1-CDK4. A potent and selective D1-CDK4 inhibitor, 7a (D1-CDK4 IC(50)=45 nM), has been identified. The potency, selectivity profile against other kinases, and structure-activity relationship (SAR) trends of this class of compounds are discussed.

Synthesis of quinolinyl/isoquinolinyl[a]pyrrolo [3,4-c] carbazoles as cyclin D1/CDK4 inhibitors.[Pubmed:12657252]

Bioorg Med Chem Lett. 2003 Apr 7;13(7):1231-5.

A novel series of pyrrolo[3,4-c] carbazoles fused with a quinolinyl/isoquinolinyl moiety were synthesized and their D1/CDK4 inhibitory and antiproliferative activity were evaluated. Compound 8H, 14H-isoquinolinyl[6,5-a]-pyrrolo[3,4-c]carbazole-7,9-dione (1d) was found to be a highly potent D1/CDK4 inhibitor with an IC(50) of 69 nM. Compound 1d also inhibited tumor cell growth, arrested tumor cells in G1 phase and inhibited pRb phosphorylation.

Indolocarbazoles: potent, selective inhibitors of human cytomegalovirus replication.[Pubmed:10428375]

Bioorg Med Chem. 1999 Jun;7(6):1067-74.

In our search for new, safer anti-HCMV agents, we discovered that the natural product Arcyriaflavin A (la) was a potent inhibitor of HCMV replication in cell culture. A series of analogues (symmetrical indolocarbazoles) was synthesised to investigate structure activity relationships in this series against a range of herpes viruses (HCMV, VZV, HSV1, and 2). This identified a number of novel, selective and potent inhibitors of HCMV, 12,13-dihydro-2,10-difluoro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol e-5,7-(6H)-dione (1d) being the best example (IC50=40 nM, therapeutic index > 1450). Compounds described in this series were generally poor inhibitors of protein kinase C betaII, and no correlation was found between the ability to inhibit HCMV and the enzyme PKC.