Molecular and crystal structures of ecteinascidins: potent antitumor compounds from the Caribbean tunicate Ecteinascidia turbinata

Some members of marine alkaloid ecteinascidins (Et's), isolated from the Caribbean tunicate Ecteinascidia turbinata, exhibit potent anticancer activity. The three dimensional structures of the N12-formyl derivative of Et729 1a and the natural N12-oxide of Et743 2 have been determined by x-ray crystallography at 0.9 A resolution. Compounds 1a and 2 crystallize in the space groups P2(1)2(1)2(1) (a = 23.214(9) A, b = 28.541(10) A and c = 13.303(9) A) and P2(1) (a = 11.720(5) A, b = 13.230(4) A, c = 28.557(5) A, beta = 90.22(2) degrees), respectively. Their crystal structures have been solved by the Patterson search method, which located the sulfur atoms permitting the phase extension. The final crystallographic R-factors are 0.059 and 0.069 for 1a and 2, respectively. There are two independent molecules, associated as a dimer, in the asymmetric unit of crystals of both 1a and 2. The structure determination allows an unequivocal assignment of the relative configuration of all the chiral centers. Assuming that ecteinascidins and safracin C (whose absolute configuration is known) have the same absolute configuration at C1 position, then the absolute configurations of various chiral positions in Ets are C1(R), N2(R), C3(R), C4(R), C11(R), C13(S), C21(S) and C22(R), respectively. The four independent Et molecules adopt two conformations in which the position of ring C relative to rings A & B is different. The molecules have a compact shape and they are conformationally strained due to a severe van der Waals clash between the sulfur atom and the aromatic ring A. By analogy to the related saframycin, the potent biological activity of Et's may be associated with their ability to form a covalent adduct to DNA using the reactive carbinolamine group. The covalent binding interaction between the Et and the N2 of guanine in the minor groove of the DNA double helix has been studied by computer modelling which suggests that rings A and B "stack" against the DNA backbone. While the bulky drug molecule makes numerous contacts with DNA, it does not significantly distort the conformation of the DNA double helix.