Folate-conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress folate receptors. In a previous study, folic acid was linked through its gamma-carboxyl group to deferoxamine (DF), and the 67Ga-labeled complex ([67Ga]DF-folate) was examined for in vivo tumor targeting efficiency in athymic mice with a human tumor cell implant. Although superb tumor-to-background contrast was obtained, slow hepatobiliary clearance would compromise imaging of abdominal tumors such as ovarian cancer. In the present study, folic acid was conjugated to an alternative chelator, diethylenetriaminepentaacetic acid (DTPA), via an ethylenediamine spacer. The desired DTPA-folate (gamma) regioisomer was synthesized by two different approaches, purified by reversed phase column chromatography, and characterized mainly by analytical HPLC, mass spectroscopy, and NMR. In cultured tumor cells, uptake of [111In]DTPA-folate (gamma) was found to be specific for folate receptor-bearing cells, and the kinetics of uptake were similar to those of free folate and other folate-conjugated molecules. In the normal rat, intravenously administered [111In]DTPA-folate (gamma) was found to be rapidly excreted into the urine, giving intestinal levels of radiotracer 10-fold lower than those observed with [67Ga]DF-folate (gamma) at 4 h. In a preliminary mouse imaging study, a folate receptor-positive KB cell tumor was readily visualized by gamma scintigraphy 1 h following intravenous administration of [111In]DTPA-folate (gamma).

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An improved procedure has been developed for the chlorosulfenylation of olefins. The method utilized is based on the quantitative reaction of aryl thiols with N-chlorosuccinimide to afford a reagent solution (A) which contains arylsulfenyl chloride as well as the "inert" co-product succinimide. Reaction of this reagent with a representative group of olefins (P-chlorophenyl sulfides in nearly quantitative yield. Aryl-substituted olefins react with reagent A in the presence of sodium carbonate to produce allylic or vinylic sulfides. The P-chloroaryl sulfides produced in the chlorosulfenylation reaction can be dehydrohalogenated with DBU to yield allyl, vinyl, or dienyl sulfides. Alternatively, the 0-chloro sulfides can be oxidized to 8-chloro sulfones, which may then be dehydrochlorinated with DBU under very mild conditions to afford excellent yields of u,d-unsaturated sulfones.Unsaturated sulfur systems are valuable weapons in the arsenal of the synthetic organic chemist. Deprotonation reactions, fostered by the propensity of the sulfur moiety to stabilize an adjacent negative charge of allyl sulfide^^,^ (la), allyl sulfoxides4 ( l b ) , a n d allyl sulfone^^,^ (IC), provide thioallylic anions (2a--c) of exceptional synthetic utility. A sulfur systems (1, 3) based upon chlorosulfenylation-dehydrochlorination reactions.

Convergent total syntheses of the extremely potent cell growth inhibitor cephalostatin 1 and two hybrid analogues, ritterostatins GN1N and GN1S, have been achieved. Ritterostatin G N 1 N displays sub-nanomolar activity in the 60 cell line human tumor panel of the National Cancer Institute. The North hemisphere of ritterazine G was efficiently constructed from hecogenin acetate in 15% yield over 13 steps. Extension of a key photolysis/Prins sequence to intermediates 19 and 32 proceeded in excellent yield, leading to installation of the Δ14 moiety in the North G and South 1 steroidal subunits. Application of a method for directed unsymmetrical coupling furnished the natural and analogue pyrazines in good yield from the cephalostatin and ritterazine components.