Efficient Asymmetric Synthesis of Tryptophan Analogues Having Useful Photophysical Properties

Two new fluorescent probes of protein structure and dynamics have been prepared by concise asymmetric syntheses using the Schöllkopf chiral auxiliary. The site-specific incorporation of one probe into dihydrofolate reductase is reported. The utility of these tryptophan derivatives lies in their absorption and emission maxima which differ from those of tryptophan, as well as in their large Stokes shifts and high molar absorptivities

Antineoplastic Agents. 600. From the South Pacific Ocean to the Silstatins

The recent advances in the development of antibody and other drug conjugates for targeted cancer treatment have further increased the need for powerful cancer cell growth inhibitors. Toward that objective we have extended our earlier discovery of the remarkable anticancer bacillistatins 1 and 2 from <i>Bacillus silvestris</i> to SAR and other structural modifications such as availability of a free hydroxy group for antibody–drug conjugate (ADC) and other prodrug linkage. That direction has resulted in seven structural modifications designated silstatins 1–8 (<b>7a</b>, <b>8a</b>, <b>8b</b>, <b>14a</b>, <b>15a</b>, <b>15b</b>, <b>18a</b>, and <b>18b</b>), where the exceptional cancer cell growth inhibition of some of them are in the range GI₅₀ 10^–3–10^–4 μM/mL. Silstatin 7 (<b>18a</b>) was converted to a glucuronic conjugate (<b>28</b>) that displayed an impressive reduction in toxicity during transport

Antineoplastic Agents. 599. Total Synthesis of Dolastatin 16

The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (<b>1</b>) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membered macrocycle employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed a key step in the synthesis. Regrettably, the synthetic dolastatin 16 (<b>1</b>), while otherwise identical (by X-ray crystal structure and spectral analyses) with the natural product, did not reproduce the powerful (nanomolar) cancer cell growth inhibition displayed by the natural isolate. Presumably this result can be attributed to conformation(s) of the synthetic dolastatin 16 (<b>1</b>) or to a chemically undetected component isolated with the natural product