The rational design and biological actions of a new class of DNA-cleaving molecules with potent and selective anticancer activity are reported. These relatively simple enediyne-type compounds were designed from basic chemical principles to mimic the actions of the rather complex naturally occurring enediyne anticancer antibiotics, particularly dynemicin A. Equipped with locking and triggering devices, these compounds damage DNA in vitro and in vivo on activation by chemical or biological means. Their damaging effects are mani-fested in potent anticancer activity with remarkable selectivities. Their mechanism of action involves intracellular unlocking and triggering of a Bergman reaction, leading to highly reactive benzenoid diradicals that cause severe DNA damage. The results of these studies demonstrate the potential of these de novo designed molecules as biotechnology tools and anticancer agents.

Microwave-assisted solid-phase organic synthesis (MASPOS) has been demonstrated to significantly facilitate the Cu(II)-or Pd(II)-mediated ring closure of the resin-bound 2-alkynylanilides. Under microwave irradiation at 200℃ [for Cu(OAc)2, NMP] or 160℃ [for Pd(MeCN)2Cl2, THF] for 10min, 1-acyl-2-alkyl-5-arenesulfamoylindoles were obtained, after cleavage from the resin, in 95-99% purities and in 65-82% overall yields via a 5-step synthetic sequence.

Cyclodeca-1,5-diyn-3-ene, the parent core of naturally occurring 10-membered ring enediyne antitumor antibiotics, decomposes at 37℃ with a t1/2 value of 18h. A prodrug approach was envisaged by in situ formation of the core structure via rearrangement of an allylic double bond. Three synthetic methods including intramolecular lithium acetylide addition to aldehyde, intramolecular Nozaki-Hiyama-Kishi reaction, and intramolecular Sonogashira cross-coupling have been established for synthesis of the enediyne precursors, (E)-3-acyloxy-4-(arylmethylidene) cyclodeca-1,5-diynes. The latter are transformed into 10-membered ring enediynes in the resence of a catalytic amount of Ln(fod)3 under mild reaction conditions. Alternatively, the enediyne precursor dissociates in buffer solution into an allylic cation or a quinone methide intermediate, which reacts with a nucleophile (such as H2O) to form the bioactive enediyne. LC-MS data confirmed formation of the 10-membered ring enediyne from the precursor, which exhibits DNA cleavage activity and cytotoxicity against P388 cancer cell line.

A novel class of nonbiaryl atropisomeric P,O-ligands possessing an N,N-dialkyl-1-naphthamide skeleton has been synthesized via an efficient chemical resolution process. It represents the first example of axially chiral P,O-ligands devoid of central chirality. Up to 94.7% ee was obtained for the Pd-catalyzed asymmetric allylic lkylation (AAA). Effects of solvent, base, and the bulk of the C8 oxygen group of the P,Oligand on the AAA reaction were examined.