acetogenins and Prostatic-Neoplasms

The high potency of the tetrahydrofuran-containing acetogenins (THF-ACGs) against a broad range of human cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-ACG mimetics in which the THF and butenolide moieties of a mono-THF-ACG were replaced with carbohydrate and thiophene residues, respectively. In the present study, towards the targeting of these carbohydrate analogues to prostate cancer (PCa), we synthesized prodrugs in which a parent thiophene or butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA), a highly specific ligand for prostate-specific membrane antigen (PSMA), which is overexpressed on prostate tumors. Both prodrugs were found to be more active against receptor positive LNCaP than receptor-negative PC-3 cells, with 2.5 and 12 times greater selectivity for the more potent thiophene analog and the less active butenolide congener, respectively. This selectivity for LNCaP over PC-3 contrasted with the behavior of the parent drugs, which showed similar or significantly higher activity for PC-3 compared to LNCaP. These data support the notion that higher activity of these DUPA-derived prodrugs against LNCaP cells is connected to their binding to PSMA and suggest that the conjugation of PSMA ligands to this family of cytotoxic agents may be effective for targeting them to PCa.

Topics: Acetogenins; Antigens, Surface; Carbohydrates; Cell Line, Tumor; Furans; Humans; Male; Prodrugs; Prostatic Neoplasms; Thiophenes

The THF containing acetogenin 4-deoxyannonmontacin (4-DAN) has attracted interest for its potent cytotoxicity against a broad range of human tumor cell lines, and relatively simple structure. Herein is described the synthesis and cytotoxicity of C-10 epimers of 4-DAN and analogues thereof comprising carbohydrate and thiophene substitutes for the THF and butenolide moieties respectively. The key synthetic ploy was the union of THF and butenolide segments or their substitutes, via an alkene cross metathesis. The different analogues showed cytotoxicity in the low micromolar to nanomolar range against the human prostate cancer cell lines LNCaP and PC3. A relatively simple mannose-linked thiophene analog was found to be similar in activity to 4-DAN.

Topics: 4-Butyrolactone; Acetogenins; Alkenes; Antineoplastic Agents; Carbohydrates; Cell Line, Tumor; Humans; Male; Mannose; Prostatic Neoplasms; Thiophenes; Trichothecenes

Bioassay-guided fractionation of the fruit powder of Graviola (Annona muricata) was continued to be conducted and yielded three more novel bioactive compounds: C-35 annonaceous acetogenins, muricins M and N, and C-37 annonaceous acetogenins, muricenin. They all contain a mono-tetrahydrofuran ring and four hydroxyl groups. The structures were elucidated by spectral methods and chemical modification after isolation via open column chromatographic separation and HPLC purification. Especially, murices M and N demonstrated more potent anti-proliferative activities against human prostate cancer PC-3 cells.

Topics: Acetogenins; Annona; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Humans; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Prostatic Neoplasms

Phytochemical complexity of plant extracts may offer health-promoting benefits including chemotherapeutic and chemopreventive effects. Isolation of 'most-active fraction' or single constituents from whole extracts may not only compromise the therapeutic efficacy but also render toxicity, thus emphasizing the importance of preserving the natural composition of whole extracts. The leaves of Annona muricata, commonly known as Graviola, are known to be rich in flavonoids, isoquinoline alkaloids and annonaceous acetogenins. Here, we demonstrate phytochemical synergy among the constituents of Graviola leaf extract (GLE) compared to its flavonoid-enriched (FEF) and acetogenin-enriched (AEF) fractions. Comparative quantitation of flavonoids revealed enrichment of rutin (~7-fold) and quercetin-3-glucoside (Q-3-G, ~3-fold) in FEF compared to GLE. In vivo pharmacokinetics and in vitro absorption kinetics of flavonoids revealed enhanced bioavailability of rutin in FEF compared to GLE. However, GLE was more effective in inhibiting in vitro prostate cancer proliferation, viability and clonogenic capacity compared to FEF. Oral administration of 100mg/kg bw GLE showed ~1.2-fold higher tumor growth-inhibitory efficacy than FEF in human prostate tumor xenografts although the concentration of rutin and Q-3-G was more in FEF. Contrarily, AEF, despite its superior in vitro and in vivo efficacy, resulted in death of the mice due to toxicity. Our data indicate that despite lower absorption and bioavailability of rutin, maximum efficacy was achieved in the case of GLE, which also comprises of other phytochemical groups including acetogenins that make up its natural complex environment. Hence, our study emphasizes on evaluating the nature of interactions among Graviola leaf phytochemcials for developing favorable dose regimen for prostate cancer management to achieve optimal therapeutic benefits.

Topics: Acetogenins; Animals; Annona; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemoprevention; Drug Synergism; Flavonoids; Humans; Male; Mice; Mice, Inbred C57BL; Phytotherapy; Plant Leaves; Plant Preparations; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Bioassay-guided fractionation of the fruit powder of graviola (Annona muricata) yielded three novel compounds: muricins J, K, and L. The compounds are all C35 Annonaceous acetogenins with a mono-tetrahydrofuran ring and four hydroxyls. Their structures were elucidated by spectral methods and chemical modification after isolation via chromatographic techniques and HPLC purification. These three acetogenins demonstrated an antiproliferative against human prostate cancer PC-3 cells.

Topics: Acetogenins; Annona; Antineoplastic Agents, Phytogenic; Cell Proliferation; Chromatography, High Pressure Liquid; Fruit; Furans; Humans; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Prostatic Neoplasms

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.

Topics: Acetogenins; Antineoplastic Agents; Drug Screening Assays, Antitumor; Furans; Humans; Leukemia-Lymphoma, Adult T-Cell; Male; Prostatic Neoplasms; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured