No abstract

Alkylation of 1 -1ithio trisubstituted glycals obtained via the corresponding I-tributylstannyl derivatives constitutes a novel entry into C-glycosides.$ All new compounds were characterized by spectroscopic and/or microanalytical data. Yields refer to chromatographically pure products. Optical rotations were measured in chloroform.

No abstract

No abstract

, 880 (1 993). Acyclic vicinal polyol complexes related to cisplatin were synthesized from D-mannitol by stereocontrolled manipulation of the hydroxy groups. Controlled cleavage of a 3,4-diazido hexitol gave the corresponding D-threitol and D-xylitol analogs, which were converted to their diamino platinum complexes. The antitumor activity of these compounds is reported.S. HANESSIAN Two decades after its discovery (I), cis-diammine dichloroplatinum(II) (cisplatin) and its structural variants (for recent reviews, see ref.2) remain as one of the most widely used group of oncolytic drugs against a variety of cancers (3) (Fig. 1). T o date, well over 1000 analogs of cisplatin have been synthesized and examined for antitumor activity, particularly against cancer of the testes, ovaries, bladder, head, and neck. Concurrently, the molecular mechanism of action of cisplatin has been the subject of intensive studies (4). The drug has been shown to bind covalently to chromosomal DNA in the cell nucleus, thus inhibiting replication (5). The site of most stable binding is at the N-7 position of guanine in the DNA, which results in the weakening of hydrogen bonding of the base pairs and the inevitable unwinding of the double helix (6).In spite of its dramatic success in the treatment of certain types of cancer (7), cisplatin has a number of drawbacks that present difficulties in its continued use. Toxicity of several types (8), narrow range of activity, cross-resistance, and lack of solubility are among the more serious limitations. A number of derivatives in which the dichloro ligands have been changed to other anionic groups (e.g., 1 ,I-cyclobutanedicarboxylato (carboplatin)) (9) have shown reduced toxicity, presumably due to better pharmacokinetic properties. Sevkral other second and third generation platinum complexes are known (2, 3).We wish to report on the synthesis and antitumor properties of a series of stereochemically defined, novel platinum complexes derived from a diaminotetritol, -pentitol, and -hexitol, having the generalized structure shown in cisplatin n = 1, 2 etc.'~u t h o r to whom correspondence may be addressed. The design of our alditol-derived platinum analogs took into consideration the distinctly superior activity of cisplatin compared to the trans isomer (1). Our synthetic plan took advantage of the C2 symmetrical properties of D-mannitol and the possibility of preparing trans-oriented vicinal diaminodideoxy derivatives therefrom. As shown in Scheme 1, a double nucleophilic displacement of the crystalline dimesylate derivative 2, employing tetra-n-butyl ammonium azide in toluene (12), gave the pivotal diazido derivative 3 as a syrup. The yield of 3 was lower when DMF or DMSO was used in the presence of sodium azide. Hydrolysis of the acetal functions led to the corresponding tetrol4, which was methylated in the usual way to give 5. Hydrogenation of 4 and 5 individually, followed by treatment of the corresponding diamino derivatives with dipotassium tetrachloroplatinate, gave the crystalline complexes...