A streamlined total synthesis of N(14)-desacetoxytubulysin H (Tb1) based on a C-H activation strategy and a short total synthesis of pretubulysin D (PTb-D43) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (Tb2-Tb41 and PTb-D42) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., Tb14), some with exceptional potencies against certain cell lines [e.g., Tb32 with IC50 = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure-activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.
A simple and efficient biomimetic synthesis of pyrrolo[1,2-a]indoles using a highly stereo- and regioselective [3 + 2] reaction cascade was developed and then further applied in the first total synthesis of flinderoles B and C, which proceeded in 17.2% yield over the longest linear sequence of 11 steps.
A simple, highly diastereoselective, Lewis acid catalyzed Friedel-Crafts coupling of a cyclic allylic alcohol with resorcinol derivatives has been developed. The method was applied for the enantiospecific total syntheses of structurally diverse natural products such as machaeriol-D, Δ(8)-THC, Δ(9)-THC, epi-perrottetinene and their analogues. Synthesis of both natural products and their enantiomers has been achieved with high atom economy, in a protecting group free manner and in less than 6 steps, the longest linear sequence, in a very good overall yield starting from R-(+) and S-(-)-limonene.
Dimeric indole alkaloids represent a structurally unique class of natural products having interesting biological activities. Recently, we reported the first total synthesis of flinderoles B and C, structurally unique and potent antimalarial natural products. Central to the design of the approach and by virtue of a one-pot, acid-catalyzed dimerization reaction, the route also provided total synthesis of the borreverine class of natural products. This full account details the progress of efforts that culminated in the protecting-group-free, six-step total synthesis of all of the flindersia alkaloids: dimethylisoborreverine, isoborreverine, flinderoles A-C, and their analogues. A biomimetic approach featuring a scalable and catalytic formal [3 + 2] cycloaddition and Diels-Alder reaction is outlined in detail. On the basis of the experimental observations, a detailed mechanism has been proposed for the dimerization of tertiary alcohol 28.
Improved, streamlined total syntheses of natural tubulysins such as V (Tb45) and U (Tb46) and pretubulysin D (PTb-D43), and their application to the synthesis of designed tubulysin analogues (Tb44, PTb-D42, PTb-D47-PTb-D49, and Tb50-Tb120), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines revealed a number of novel analogues with exceptional potencies [e.g., Tb111: IC = 40 pM against MES SA (uterine sarcoma) cell line; IC = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC = 1.54 nM against MES SA DX (MES SA with marked multidrug resistance) cell line]. These studies led to a set of valuable structure-activity relationships that provide guidance to further molecular design, synthesis, and biological evaluation studies. The extremely potent cytotoxic compounds discovered in these investigations are highly desirable as potential payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.
Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products.
An efficient taurine-catalyzed
green multicomponent approach has
been described for the first time to synthesize densely substituted
therapeutic core dihydropyrano[2,3-c]pyrazoles. Applications
of the developed synthetic strategies and technologies revealed the
synthesis of a series of newly designed 1,4-dihydropyrano[2,3-c]pyrazoles containing isonicotinamide, spirooxindole, and
indole moieties. Detailed in silico analysis of the
synthesized analogues revealed their potential to bind wild-type and
antibiotic-resistant variants of dihydrofolate reductase, a principal
drug target enzyme for emerging antibiotic-resistant pathogenic Staphylococcus aureus strains. Hence, the synthesized
dihydropyrano[2,3-c]pyrazole derivatives presented
herein hold immense promise to develop future antistaphylococcal therapeutic
agents.
An ecofriendly, inexpensive,
and efficient route for synthesizing
3,3′-bis(indolyl)methanes (BIMs) and their derivatives was
carried out by an electrophilic substitution reaction of indole with
structurally divergent aldehydes and ketones using taurine and water
as a green catalyst and solvent, respectively, under sonication conditions.
Using water as the only solvent, the catalytic process demonstrated
outstanding activity, productivity, and broad functional group tolerance,
affording the required BIM natural products and derivatives in excellent
yields (59–90%). Furthermore, in silico based structure activity
analysis of the synthesized BIM derivatives divulges their potential
ability to bind antineoplastic drug target and spindle motor protein
kinesin Eg5. The precise binding mode of BIM derivatives with the
ATPase motor domain of Eg5 is structurally reminiscent with previously
reported allosteric inhibitor Arry520, which is under phase III clinical
trials. Nevertheless, detailed analysis of the binding poses indicates
that BIM derivatives bind the allosteric pocket of the Eg5 motor domain
more robustly than Arry520; moreover, unlike Arry520, BIM binding
is found to be resistant to drug-resistant mutations of Eg5. Accordingly,
a structure-guided mechanism of Eg5 inhibition by synthesized BIM
derivatives is proposed.
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