a) 5 mol% PdCl₂(PPh₃), 10 mol% CuI, Et₃N, THF; b) 2 mol% Pd(PPh₃)₄, Bu₃SnH, THF, 0 °C; c) 10 mol% Pd(PPh₃)₄, 20–100 mol% CuI, CsF, DMF, 60 °C.

Another series of ADAMs has recently been developed by scientists at Celgene Corp. as potent inhibitors of inflammation, phosphodiesterase type 4 activity, and tubulin polymerization, where tubulin inhibition involves binding of the inhibitor to the same site as the natural antimitotic agent, colchicine (3, Chart 1).10–13 The structural similarity between Celgene’s inhibitor CC-5079 (Chart 1) and our own antiviral agents led us to consider that the ADAMs may also exhibit one or more of the properties displayed by the Celgene inhibitors. It is well known that disrupting microtubule homeostasis causes cells to undergo apoptosis11, and the low micromolar toxicity generally displayed by the ADAM class of NNRTIs led to the hypothesis that the ADAMs’ cytotoxic properties may originate from the inhibition of tubulin polymerization by binding to the colchicine binding site. Additionally, inhibition of tubulin polymerization may also account for the RT-independent antiviral activity displayed by many ADAM analogues. The vital HIV protein Tat is known to, among other things, stabilize the microtubule framework of HIV-infected cells by binding to microtubule-associated protein (MAP) binding sites.14 It has been proposed that the interactions between Tat and microtubules help facilitate the replication of HIV and may also contribute to the mechanism of HIV-related cell death.14 In light of this information, the inhibition of tubulin polymerization by a select group of ADAMs was investigated. Herein we report the syntheses, antiviral activity, and tubulin inhibitory effects of ADAMs 4–17.