Chronic hepatitis C virus (HCV) infection affects millions of people worldwide and is associated with cancer. Direct-acting antivirals (DAAs) have changed HCV treatment paradigms, but little is known about management of HCV infection in patients with cancer. The substantial burden of HCV infection in patients with cancer and the inconclusive evidence regarding detection and management of HCV infection in patients with cancer prompted us to review the literature and formulate recommendations. Patients for whom HCV screening is recommended included all patients with hematological malignancies, hematopoietic cell transplant candidates or patients with hepatocellular carcinoma (HCC). There is lack of consensus-based recommendations for the identification of other cancer patients but physicians may consider screening patients belonging to groups at heightened risk of HCV infection including persons born during 1945–1965 and those at high risk for infection. Patients with evidence of HCV infection should be assessed by an expert to evaluate liver disease severity, comorbidities associated with HCV infection, and treatment opportunities. DAA therapy should be tailored on the basis of patient prognosis, type of cancer, cancer treatment plan, and hepatic and virologic parameters. HCV-infected cancer patients with cirrhosis (or even advanced fibrosis) and those at risk for liver disease progression, especially patients with HCV-associated comorbidities, should have ongoing follow-up, regardless of whether there is a sustained virologic response, to ensure timely detection and treatment of HCC. HCV infection and its treatment should not be considered contraindications to cancer treatment and should not delay the initiation of an urgent cancer therapy.

The interaction between leukocyte function-associated antigen-1 (LFA-1), a member of the beta(2)-integrin family of adhesion molecules, and intracellular adhesion molecule ICAM-1 (cd54) is thought to play a critical role in the inflammatory process. On the basis of an anilino diaryl sulfide screening lead 1, in combination with pharmacophore analysis of other screening hits, we have identified an adjacent binding pocket. Subsequently, a p-ethenylcarbonyl linker was discovered to be optimal for accessing this binding site. Solution-phase parallel synthesis enabled rapid optimization of the cinnamides for this pocket. In conjunction with fine-tuning of the diaryl substituents, we discovered a novel series of potent, nonpeptide inhibitors of LFA-1/ICAM-1 interaction, exemplified by A-286982 (28h), which has IC(50) values of 44 and 35 nM in an LFA-1/ICAM-1 binding assay and LFA-1-mediated cellular adhesion assay, respectively.

The first total syntheses of higher-order members of the polypyrrolidinoindoline alkaloid family are reported. The synthesis of quadrigemine C (1) and psycholeine (3) begins with synthetic meso-chimonanthine (4), which is synthesized from commercially available oxindole and isatin in 13 steps and 35% overall yield. Double Stille cross coupling of diiodide 7, available in three steps from 4, with vinylstannane 8 produces dibutenanilide 9. Double catalytic asymmetric Heck cyclization of 9 simultaneously installs the two peripheral quaternary stereocenters and desymmetrizes this advanced meso precursor to deliver the chiral, decacyclic intermediate 11 in 62% yield and 90% ee. In two additional steps, 11 is converted to 1, which upon treatment with acid generates 3. The synthesis of quadrigemine C (1), which rigorously confirms its relative and absolute configuration, was executed in 19 linear steps (2% overall yield) from commercially available starting materials.

21.tleri\wl from doubly MOM-protected homophthalic anhydride 20. followed by oxidation with phenyliodondium bis(tritluoroacetaie) resulted in a substance which we provisionally formulate a\ 22.""' The proposal advanced in Scheme 5 for the progression from 16 to 22 should be implemented in a formal ruilier than ;I chronological context. When a highly concentrated solution of 22 in T H F was exposed to the action of oxygen : m i daylii~ht. ; t violet-red product presumed to be the protected goal structure 23 was obtained.li5] Deprotection of 23 afforded dynemicin A (1). The ' H NMR spectrum and TLC properties of thc synthetic material matched those of an authentic sample. The relative configuration at C-4 had been independently veritied h! ci-~stallography at an earlier stage."' The comparisons with the severely limited authentic material available. the nature of the s t e p . and the inherent properties of our final product, fully establish that ( & )-dynemicin A ( 1 ) had been synthesized.Studies directed to higher yielding anthraquinone annulation protocols are underway. Also, with increased quantities of dyncinicin nou available to us by synthesis, investigations of sonic ofihe bioorganic issues identified above have already been initiated . Receivcd: April 20. I Y Y S [Z79131E] 18x5 (iei-niaii \crsion: A/i,qc.~. C h r i . 1995. 1117. I XX3

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