Hypocrellins

4 Hypocrellins. - This family of fungal perylenequinonoids is being explored 

EPR and ENDOR spectra of the semiquinones from a series of hypocrellin derivatives have been obtained following chemical and electrochemical reduction.  

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Although the majority of metal complexes developed for PDT have porphyrin-style ligands, there are exceptions (e.g., compounds (53) and (54) to (57)). The aluminum(III) complex of hypocrellin B (59) provides another example. Compound (59) is an oligomeric system where n is about 9 the material is water soluble, has Amax(DMSO) 614 nm, and generates both superoxide and singlet oxygen on irradiation ([Pg.987]

The hypocrellins (7-9) are Class B perylenequinones that have also been the subject of much investigation due to their biological activity, having been used in Chinese folk medicine for the treatment of vitiligo, psoriasis, and other diseases for... 

In addition to cercosorin, other photoactive members of class B include calphostins A-D (4a-d), isolated from Cladosporium cladosporioides [10] phleichrome (5), isolated from Cladosporium phlei [11] and the elsinochromes (6) [12], isolated from several species of the genus Elsinoe. In this chapter, background on the syntheses and biological activity of the calphostins and phleichrome is included, because of their structural similarity to hypocrellin and cercosporin. 

The problems of high lipophilicity and subsequent low bioavailability of the perylenequinones have been approached by altering their formulations [23]. Another limitation to the use of perylenequinones as therapeutic agents is the poor extinction coefficient in the longer wavelength of light (650-800 nm) that is needed to penetrate deep tissue. Many derivatives of hypocrellin have been... 

The barrier to atropisomerization is also lower for the hypocrellins due to introduction of the seven-membered ring bridging the Cl,Cl -positions. In fact, hypocrellin A (7) and hypocrellin (ent-1) both exist as rapidly atropisomerizing mixtures of diastereomers at room temperature, as revealed by NMR studies by Mondelli. Here, two sets of sharp peaks of the resultant diastereomers are observed in the NMR spectra of each natural product [35]. Figure 7.2 presents the structures of hypocrellin A (7) and its atropisomer, atrop-1, which exist as an equilibrium... 

With a synthesis of 58 completed, the key intramolecular diketone aldol cyclization was investigated. Precedent for this type of 1,8-dicarbonyl aldol reaction is rare, although an aldol reaction has been proposed in the biosynthetic pathway to the hypocrellins. The only reported examples of such diketone aldol cyclizations involve multicyclic or bridged bicyclic systems, and of these no examples exist for 1,8-diketones forming 7-membered rings. MM2 calculations indicated that a... 

Scheme 7.15 Diketone aldol transition states to hypocrellin A...

Z)-enolate of 58 would adopt a closed chair-like transition state that favored exposure of one face of the ketone by 1.5 kcal/mol, leading to the vyn-aldol product corresponding to hypocrellin A (Scheme 7.15). 

Exposure of 58 to LiN(SiMe2Ph)2 at —105 °C provided the aldol product with the desired 7-membered ring present of the hypocrellins (Scheme 7.16). This yvn-aldol adduct was anticipated from a (Z)-enolate and silazide bases give predominately... 

Z)-enolates. The product was subjected to selective deprotection of the C4,C4 -methyl ethers with Mgl2, providing the natural structure of hypocrellin A as the major product. The two newly formed stereocenters in the 7-membered ring were determined to conform to the predicted helical (/ -stereochemistry and the syn-aldol stereochemistry. The minor ( )-enolate afforded the anti aldol product, which matched the diastereomeric natural product shiraiachrome A (8). With this step, the first total syntheses of hypocrellin A and shiraiachrome A (symanti = 10 1 syn diastereomer, 92 % ee) were completed. 

The development of new synthetic methodology has successfully enabled the investigation of structure-activity relationships (SAR) of perylenequinone agents for use in photodynamic therapy. Simplified analogs, such as (M)-96, that have potency equal to the natural product hypocrellin and superior chromophores to improve photoactivation in the therapeutic window were prepared. 

Hypocrellin (ent-1) Chen WS, Chen YT, Wang XY, Friedrichs E, Puff H, Breitmaier E (1981) Liebigs Ann Chem 1880-1885... 

Kishi T, Tahara S, Tsuda M, Tanaka C, Takahashi S (1991) Planta Med 57 376-379 (shiraiachrome A is called hypocrellin B here)... 

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