Studies on antitumor cyclic hexapeptides RA obtained from Rubiae Radix, Rubiaceae. III. On derivatives of RA-V and their in vivo activities.

With the aim of obtaining compounds with strong antitumor activity and weak toxicity, we have synthesized a series of alkylethers, fatty acid esters, benzoates and other derivatives of RA-V, an antitumor cyclic hexapeptide discovered in Rubiae Radix, and examined their antitumor activities against P-388 lymphocytic leukemia. It was found that the introduction of C1 and C6 chains (hydrophobic coefficient log P=about 3.2 and 5.8, respectively) on the phenol moiety of RA-V gave the most desirable compounds in terms of antitumor activity and toxicity. The caproic ester of RA-V, the n-hexylether of RA-V and RA-VII (C1) also exhibited strong antitumor activity against other experimental tumors (L-1210 lymphocytic leukemia, B-16 melanoma and MM2 mammary carcinoma).