Cancer fighting cancer: synthesis of the new heterocyclic system diimidazo-[1,2-a :1,2-c ]-pyrimidine 1

One of our projects devoted to the synthesis of potential antitumor agents is called “Cancer Fighting Cancer”. This brought us to synthesize the new heterocyclic system, diimidazo-[1,2-a:1,2-c]-pyrimidine, which is a key intermediate for the synthesis of antitumor derivatives. The structure of this compound was demonstrated by means of NMR and MS experiments .


Introduction
In 1977 we published our first paper on the synthesis of potential antitumor agents. 2 The last one (number 32 of this series) has been published recently. 3We called one of our projects, "Cancer Fighting Cancer" implying our search for molecules wherein a well known pharmacophoric group is duplicated.We envisioned such two-weaponed drugs as fighting cancer like a crab fights off enemies with its nippers.

Figure 1
On the other hand, starting from 2,4-diaminopyrimidine we were able to prepare the intermediate for our first target compound, as illustrated in Figure 4.

Chemistry
The crystal structure of compound 6 (R=phenyl) is depicted in Figure 3.It has allowed us to unambiguously identify and structurally characterize the product of the reaction of 3 (R=phenyl) with 2-bromoacetophenone.
Two independent molecules of 6 form the asymmetric unit.In the thiadiazole moiety the bond lengths are close to that found in analogous derivatives. 6As an example, the distance N-N is equal to 1.396(9) and 1.379(8) Å in the two molecules of the asymmetric unit The planar imidazothiadiazole ring and its appended phenyl group form dihedral angles of 39.1 and 43.2º, respectively, in the two molecules of the asymmetric unit.The phenyl bound to the CH 2 -CO group is close to being orthogonal to the imidazothiadiazole ring, with dihedral angles equal to 75.26 and 71.40° in the two molecules of the asymmetric unit.
The crystal structure is stabilized by intermolecular hydrogen bonds and stacking interactions.One of these latter involves the thiadiazole moiety of one molecule and the phenyl ring bound at position 6 of the other molecule of the asymmetric unit.The distance between the two ring centroids is 3.61Å, while the dihedral angle between the two planes is 11°.The mean distances between the amino groups and bromines (N…Br) are 3.37Å.
An attempt to prepare 11 directly from 7 with excess of 2-bromoacetophenone was unsuccessful: the intermediate 8 is formed as the hydrobromide and it was necessary to prepare the corresponding base before treating it again with 2-bromoacetophenone.

Conclusions
Compound 11 was then functionalized in order to obtain bis-weaponed molecules, analogous to that reported in Figure 1.The first of those derivatives was submitted to the National Cancer Institute (Bethesda, MD) with the NSC number 720134.It was active in the panel of three human tumor cell lines and is now under evaluation in the full panel of sixty cell lines. 7he chemistry of this compound will be published as soon as the biological data are available.

Experimental Section
General Procedures.Melting points are uncorrected.Analyses (C, H, N) were within ±0.4% of the theoretical values.Bakerflex plates (silica gel IB2-F) were used for TLC: the eluent was petroleum ether/acetone 50/50.The IR spectra were recorded in Nujol on a Nicolet Avatar 320 E.S.P.; ν max is expressed in cm -1 . 1 H-NMR spectra were recorded in (CD 3 ) 2 SO on a Varian Gemini (300 MHz); the chemical shift (referenced to solvent signal) is expressed in δ(ppm) and J in Hz with the following abbreviations: ar=aromatic, pym=pyrimidine, im=imidazole.MS and MS/MS spectra were obtained by using a ThermoFinnigan LCQDeca instrument operating with electrospray ionization.-6-phenylimidazo-[1,2-d]-[

X-ray crystallography of 6 (R=phenyl).
Single crystals of 6 were obtained by dissolving some mg of powder in EtOH and allowing the solution to evaporate at room temperature.A Siemens P4 four-circle diffractometer with graphite monochromated Mo-Kα radiation (λ = 0.71073Å) and the ω/2θ scan technique were used for data collections.The structure was solved by direct methods implemented in the SHELXS-97 program. 8The refinement was carried out by fullmatrix anisotropic least-squares on F 2 for all reflections for non-H atoms by using the SHELXL-97 program. 9Crystal data are reported in Table 1.