Synthesis and convenient functionalisation of pyridazinofurocoumarins: nitrogenated isosters of potent DNA inhibitors Jose ´ Carlos Gonza ´lez-Go ´mez, Lourdes Santana and Eugenio Uriarte * Departamento de Quı ´mica Orga ´ nica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain Received 3 June 2003; revised 11 August 2003; accepted 20 August 2003 Abstract—Pyridazino[3,4-h]psoralens and pyridazino[3,4-j]angelicins are prepared in good yield from resorcinols through a direct, easy and generally applicable synthetic route. The key step in this route is the inverse electron-demand Diels – Alder reaction between linear or angular furocoumarins and 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine to give the dicarboxymethylated tetracycles. The ester group in the peri position with respect to the oxygen in the furan ring can be regioselectively transformed to give primary or secondary amides. Similarly, the two ester groups in the tetracycle can be transformed in a high-efficiency process to give bis-amides that can be either symmetrical (from the same amine) or unsymmetrical (from two different amines). q 2003 Elsevier Ltd. All rights reserved. 1. Introduction Furocoumarins form a group of natural or synthetic compounds that are of great pharmacological interest. One of the most important applications of these compounds is in the field of photochemotherapy, where furocoumarins are capable of undergoing photoaddition with thymine units present in DNA. However, the most effective compounds in this class are associated with side-effects, mainly related to their ability to stabilize bridging bonds between the strands of the DNA helix. 1 One of the most promising strategies to obtain monofunctional furocoumarins efficiently involves incorporating one of the reactive double bonds in a benzene nucleus by forming benzofurocoumarins (Chart 1). This approach results in molecules that have a high propensity for intercalation and photoreaction with DNA and also helps to overcome some of the negative phototoxic effects. 2,3 With this information in mind, it was decided to investigate the effect of introducing nitrogen atoms into the polycyclic skeleton on the basis that this could increase the stability of the complex formed by the interaction of the molecule with DNA. 4 This aim could be achieved by replacing the fourth benzene ring in the benzofurocoumarin system with a pyridazine, which would be attached to the furan ring through its 4,5-bond. We have previously obtained tetracyclic skeletons of this type through inverse electron- demand Diels – Alder reactions between a furocoumarin and the particularly reactive compound 3,6-bis(trifluoromethyl)- 1,2,4,5-tetrazine. 5 However, for the current target it is necessary to easily and conveniently functionalise one or both positions adjacent to the nitrogen atoms of the pyridazine ring. This aspect is important because equivalent positions are substituted with different chains in a range of tricyclic and tetracyclic compounds that are known to intercalate with DNA. 6 Chains bearing an amide function are amongst the most widely used in this type of intercalating anticancer compound. For this reason, the diene chosen for the Diels – Alder reaction with linear and angular furocoumarins was the 3,6-dicarboxymethyl-substituted tetrazine. It was then planned to investigate the possible amidation of one or both ester groups in the resulting tetracycles. Pyrrolidine 0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2003.08.051 Tetrahedron 59 (2003) 8171–8176 Chart 1. Tetracyclic skeleton of a benzo[j]angelicin I and a benzo[h]- psoralen II. * Corresponding author. Tel.: þ34-981563100; fax: þ34-981594912; e-mail: qofuri@usc.es Keywords: furocoumarins; DNA inhibitors; Diels– Alder reaction.