Structure-Activity Relationships of Thiophene Carboxamide Annonaceous Acetogenin Analogs: Shortening the Alkyl Chain in the Tail Part Significantly Affects Their Growth Inhibitory Activity against Human Cancer Cell Lines.

In a previous study, we found that the thiophene carboxamide solamin analog, which is a mono-tetrahydrofuran annonaceous acetogenin, showed potent antitumor activity through the inhibition of mitochondrial complex I. In this study, we synthesized analogs with short alkyl chains instead of the n-dodecyl group in the tail part. We evaluated their growth inhibitory activities against human cancer cell lines. We found that the alkyl chain in the tail part plays an essential role in their activity.

Muricatacin, a Gateway Molecule to Higher Acetogenin Synthesis.

In this review, we have abstracted the various syntheses of acetogenins where the start point has been muricatacin. The latter can best be synthesized in either enantiomer form by the Sharpless method in three steps and can be admired as a gateway molecule for a quick assembly of many higher acetogenins. Muricatacin with orthogonally differentiated hydroxy groups and the available lactone carbonyl for chain elongation/modification can enable the concise synthesis of higher acetogenins. Many closely related synthetic intermediates possible from muricatacin are also abstracted here. The review should give impetus for future synthetic endeavours where the start point could be muricatacin and at least to the new molecules that are yet to be synthesized.

Total Synthesis of (+)-Goniodenin.

Goniodenin is a lipophilic polyketide originating from plant sources and which possesses a potent cytotoxic activity against cancer cell lines. The first total synthesis of (+)-goniodenin has been achieved in 23 steps from (R)-glycidol. The synthetic sequence featured a cross metathesis for the formation of the C8-C9 bond and installation of the terminal γ-butenolactone ring unit by the alkylation of α-phenylthio-γ-butyrolactone with the corresponding C3-O-triflate. The stereogenic center at C18 carbon was created by Hiyama-Fujita reduction of the corresponding ketone with high diastereoselectivity.

Total Synthesis of the Proposed Structure for Aromin and Its Structural Revision.

This paper describes the first total synthesis of the proposed structure for aromin, an annonaceous acetogenin possessing an unusual bis-THF ring system, and its 4S,7R-isomer. The key steps involve an oxidative cyclization of a couple of terminal-diene alcohols and an intermolecular metathesis of an alkenyl tetrahydrofuran with an enone carrying a tetrahydrofuranyl lactone. The spectral data of both samples did not match those of aromin. Re-examination of the NMR data using the CAST/CNMR Structure Elucidator and chemical derivations suggested that the real structure of aromin should be revised to be a tetrahydropyran acetogenin, montanacin D. Cytotoxicities in human solid tumor cell lines for synthetic samples were also evaluated.

Short Route to the Total Synthesis of Natural Muricadienin and Investigation of Its Cytotoxic Properties.

An original synthesis of the acetogenin muricadienin, the bioprecursor of solamin, has been developed. The key step in the five-step 41% overall yield synthesis is the catalytic cross-cyclomagnesiation reaction of functionally substituted 1,2-dienes with EtMgBr in the presence of Cp2TiCl2 and magnesium metal. It has been demonstrated for the first time that muricadienin exhibits a moderate in vitro inhibitory activity against topoisomerases I and IIα, key cell cycle enzymes. Using flow cytometry, muricadienin was shown to have high cytotoxicity toward the HEK293 kidney cancer cells (IC50 0.39 µM).

Synthesis of dansyl-labeled probe of thiophene analogue of annonaceous acetogenins for visualization of cell distribution and growth inhibitory activity toward human cancer cell lines.

The convergent synthesis of the dansyl-labeled probe of the thiophene-3-carboxamide analogue of annonaceous acetogenins, which shows potent antitumor activity, was accomplished by two asymmetric alkynylations of the 2,5-diformyl THF equivalent with an alkyne having a thiophene moiety and another alkyne tagged with a dansyl group. The growth inhibitory profiles toward 39 human cancer cell lines revealed that the probe retained the biological function of its mother compound, and would be useful for studying cellular activity.

Thiophene-3-carboxamide analogue of annonaceous acetogenins as antitumor drug lead.

Five novel acetogenin analogues with a furan, thiophene, or thiazole ring were synthesized, and their inhibitory activities toward human cancer cell lines were evaluated. The analogues showed more potent activities than natural acetogenin. One of them, the thiophene-3-carboxamide analogue, strongly inhibited the growth of human lung cancer cell line NCI-H23 in the xenograft mouse assay without critical toxicity.

Identification of novel bivalent mimetics of annonaceous acetogenins via a scaffold-hopping strategy.

A series of novel bivalent mimetics of annonaceous acetogenins have been designed, synthesized, and evaluated. Among these, compound 7 bearing a homopiperazine ring in the middle region exhibited more potent growth inhibitory activity and higher selectivity against cancer cells over normal cells by comparison with AA005. This work indicates that modification of the middle piperazine ring is a useful optimizing tool for the simplified acetogenin mimetics.

Synthesis and tumor cell growth inhibitory activity of biotinylated annonaceous acetogenins.

Nineteen biotinylated squamocin/bullatacin derivatives have been synthesized for targeted delivery to biotin receptor overexpressed tumor cells. Most biotinylated squamocin and bullatacin derivatives show similar in vitro cytotoxicity against the biotin receptor non-overexpressed L1210 cells as squamocin and bullatacin, respectively, while against biotin receptor overexpressed 4T1 and P815 tumor cells, several derivatives show significantly higher potency and better selectivity. Among all the synthesized compounds, 15,28-di-O-(6-biotinylamidohexanoyl)squamocin (16) is the most potent, which is 10 and 26 times more active than squamocin against 4T1 and P815 cells, respectively. Compound 16 also appears to be six and fifteen times more selective than squamocin towards 4T1 and P815 cells, respectively, against L1210 cells. The structure activity relationship analysis has revealed that the preferred site for biotinylation is different for squamocin and bullatacin, and it also depends on whether a linking spacer is present.

Synthesis and anti-tumor activity of carbohydrate analogues of the tetrahydrofuran containing acetogenins.

The tetrahydrofuran (THF) containing annonaceous acetogenins (AAs) are attractive candidates for drug development because of their potent cytotoxicity against a wide range of tumors and their relatively simple and robust structures. Replacement of the THF segment with a sugar residue may deliver analogues with improved tumor selectivity and pharmacokinetics and are therefore attractive for drug development. As a first test to the feasibility of such structures, a set of such monosaccharide analogues was synthesized and assayed against four human tumor cell lines, cervical (HeLa), breast (MDA-MB231), T-cell leukemia (Jurkat) and prostate (PC-3). Certain analogues showed low micromolar activity that was comparable to a structurally similar, naturally occurring mono-THF acetogenin. A preliminary examination of the structure-activity profile of these carbohydrate analogues suggests that they have a similar mechanism of action as their THF congeners.

Total synthesis, stereochemical assignment, and biological activity of chamuvarinin and structural analogues.

A highly stereocontrolled synthesis of (+)-chamuvarinin has been completed in 1.5% overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin-Anh control), followed by the two step activation/cyclization to close the C20-C23 2,5-cis-substituted tetrahydrofuran ring and a Julia-Kocienski olefination at C8-C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2% overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness.

Synthesis of bioactive natural products as protein inhibitors.

Synthetic studies of Annonaceous acetogenins isolated from the plant family Annonaceae and marine natural products (miraziridine A, tokaramide A, and callipeltins) containing unusual amino acids, and recent studies of the structure-activity relationship of cysteine protease inhibitor are described.

Design and synthesis of C35-fluorinated solamins and their growth inhibitory activities against human cancer cell lines.

The convergent synthesis of C35-fluorinated analogues of solamin, a mono-THF Annonaceous acetogenin, has been achieved by the Sonogashira coupling of the THF ring fragment and the fluorinated γ-lactone fragment. It was revealed that the number of fluorine atoms on the γ-lactone moiety affects the growth inhibitory activities against human cancer cell lines.

Potent antitumor mimetics of annonaceous acetogenins embedded with an aromatic moiety in the left hydrocarbon chain part.

Annonaceous acetogenins are a large family of naturally occurring polyketides exhibiting remarkable anticancer activities. The first generation of annonaceous acetogenin mimetic (1, AA005) exhibits comparable activity as that of natural products and presents much higher selectivity between cancer and normal cells. In this work, we report the design, synthesis, and evaluation of a new series of compound 1 analogues in which a variety of conformation-constrained fragments were embedded in the left hydrocarbon chain part. Compound 7 bearing a biphenyl moiety was identified to exhibit more potent antiproliferative activity and preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.

Convergent synthesis of fluorescence-labeled probes of Annonaceous acetogenins and visualization of their cell distribution.

The convergent synthesis of fluorescence-labeled solamin, an antitumor Annonaceous acetogenin, was accomplished by two asymmetric alkynylations of 2,5-diformyl tetrahydrofuran with an alkyne tagged with fluorescent groups and another alkyne with an α,ß-unsaturated γ-lactone. Assay for the growth inhibitory activity against human cancer cell lines revealed that the probe with the fluorescent groups at the end of the hydrocarbon chain may have the same mode of action as natural acetogenins. The merged fluorescence of dansyl-labeled solamin and MitoTracker Red suggests that Annonaceous acetogenins localize in the mitochondria.

Synthesis and antitumor activity of C-9 epimers of the tetrahydrofuran containing acetogenin 4-deoxyannoreticuin.

A highly convergent synthesis of mono-tetrahydrofuran (THF) containing acetogenins, that is based on the cross-metathesis of THF and butenolide alkene precursors, was developed. This methodology was applied to the epimers of the C-9 alcohol of 4-deoxyannoreticuin, in an attempt to assign the configuration at this position in the naturally occurring material. Unfortunately, identification of one or the other epimeric structures with the natural product was not possible because of the closeness of the physical data for all three compounds. Both C-9 epimeric analogues showed similar cytotoxicity in the low micromolar range, against two human tumor cell lines PC-3 (prostate) and Jurkat (T-cell leukemia). This result contrasts to previous studies on closely related THF acetogenins, wherein configurational variation at analogous carbinol centers resulted in a significant effect on antitumor activity.

Current topics of organic and biological chemistry of annonaceous acetogenins and their synthetic mimics.

Annonaceous acetogenins are a large family of natural polyketides. So far, more than 430 compounds have been isolated. Biologically, they are among the most potent of the known inhibitors of complex I (NADH-ubiquinone oxidoreductase) in mitochondrial electron transfer system. Herein, we would like to conduct an overview on the progress of the total synthesis, structural revisions, structure activity relationship for the inhibition of complex I, and action mechanism.

Synthesis of hybrid acetogenins, alpha,beta-unsaturated-gamma-lactone-free nitrogen-containing heterocyclic analogues, and their cytotoxicity against human cancer cell lines.

A series of alpha,beta-unsaturated-gamma-lactone-free nitrogen-containing heterocyclic analogues of solamin, a natural mono-THF acetogenin, have been synthesized and their cytotoxicity was investigated against 39 tumor cell lines. One of them, 1-methylpyrazol-5-yl derivative, showed selective increase of cytotoxicity against NCI-H23 with 80 times higher potency than solamin.

Synthesis of annonaceous acetogenins from muricatacin.

Synthetic studies of annonaceous acetogenins starting from (-)-muricatacin (1a) or (+)-muricatacin are described, involving (-)-muricatacin (1a), mono-THF acetogenin, solamin (2), reticulatacin (3), (15R, 16R, 19S, 20S)-cis-solamin (4a) and (15S, 16S, 19R, 20R)-cis-solamin (4b), non-adjacent bis-THF acetogenin, 4-deoxygigantecin (5), and epoxide-bearing acetogenin, (15S, 16R, 19S, 20R)-diepomuricanin (6a).