|其他摘要||This dissertation is composed of four chapters. The total synthesis of racemic Gomisin M1 and its biphenyl derivatives are described in Chapter One, in which studies towards anti-HIV activity of the synthesized compounds are also presented. Studies on the synthesis and bioactivities of eriocalyxin B derivatives are described in Chapter Two. The total synthesis of Przewalskin B was reported in Chapter Three. In Chapter Four, a review of strategies used previously for the total synthesis of dibenzocyclooctadiene lignans is provided.
Gomisin M1 is a dibenzocyclooctadiene lignan isolated firstly from the Chinese medicinal herb Schisandra chinensis. In our previous research for natural products as anti-HIV agents, Gomisin M1 showed significant activity, with CC50, EC50 and TI values of 26.91μg/mL, 0.12 μg/mL and 178.61, respectively. Compared racemic Gomisin M1 (with similar activity, TI=144.18) to its natural counterpart, we found that the biphenyl configuration had little effect on the antiviral activity of dibenzocyclooctadiene lignans. Encouraged by this result, we synthesized a number of biphenyl derivatives with simplified structure. To our delight, compound 24 demonstrated the best inhibitory activity against HIV-1 (EC50=0.18μg/mL，TI=257.60) with low toxicity (CC50=85.31μg/mL, TI=473.94), and exerted protective activity on HIV-1 infected MT-4 host cells from dying with TI values of >196.08. Compound 24 might deserve as a promising candidate for further biological evaluation.
Eriocalyxin B is a diterpene compound isolated from Isodon eriocalyx (Dunn) Hara, and possesses significant antitumor activities. In chapter 2, we mainly focused on the modification of the B ring system of eriocalyxin B by attaching a lipophilic alkyl side chain to the C-6 hydroxyl group. Ten derivatives were synthesized, and evaluated against five tumor cell lines (BEL-7402, A549, HT-29, HL60, MOIL-4), moderate activities were observed. However, all derivatives were less potent than its parent compound-eriocalyxin B. Our results suggest that the moiety of α, β-unsaturated ketone in A-ring also plays a role in the anti-tumor activity. In the absence of the A-ring α, β-unsaturated ketone unit, all derivatives showed reduced activities.
Przewalskin B is a diterpene with a [5, 6] spiro ring firstly isolated from Salvia Przewalskii Maxim, and possesses moderate anti-HIV-1 activity (EC50=30.32μg/mL，SI=3.32). The synthesis of B, C, D ring of model molecule (compound 12) was completed using cyclohexanone as starting material. Another route towards the synthesis of Przewalskin B was performed using isobutyraldehyed and methyl vinyl ketone (MVK) as starting material, and A, B ring was established through a Diels-Alder reaction.
New reagents and methods utilized in the total synthesis of dibenzocyclooctadiene lignans are reviewed (from 1990 to 2008).|