Preparation of Tricyclic Lactam Model Compounds of Renieramycin and Saframycin Anticancer Natural Products from Common Intermediate

Abstract

Tricyclic lactam model compounds of the left half (ABC ring) of renieramycin and saframycin anticancer natural products were prepared from common intermediate 6a. Readily available alcohol 6a was converted into enamide 8, and this was followed by transformation into 6b through a hydrobromination reaction in a stereoselective manner. Some diastereomers at C-6 to C-11a of the tricyclic lactam model compounds having several functional groups at C-6 were prepared from 6a or 6b in good yields. We presented also an unexpected reductive acetylation of the p-quinone to produce the corresponding 3,4-dehydro derivative.Key words renieramycin; saframycin; tetrahydroisoquinoline; hydrobromination; preparation; reductive acylation Tetrahydroisoquinoline natural products, including renieramycins, saframycins, ecteinascidins, naphthyridinomycins, and quinocarcins, have persistently attracted considerable interest for more than 30 years due to their novel structures and meager availability in nature, as well as their potent antitumor activity 1,2) ( Fig. 1). Ecteinascidin 743, in particular, has received considerable attention for its strong in vivo activity.3)It is currently marketed in over fifty countries for the treatment of soft-tissue sarcoma and phase II/III clinical trials for the treatment of other cancers are ongoing. 4,5) In the course of our research of new metabolites from marine animals, we isolated renieramycin M in gram scale from the Thai blue sponge Xestospongia sp. by pretreatment with potassium cyanide.6,7) Structure-activity relationship (SAR) investigations of a variety of derivatives of renieramycin M 8-10) yielded several pieces of evidence pointing to the fact that virtually all biologically active members of this family of natural products, such as 1, possess a carbinolamine or cyano function at C-21, which permits the formation of potent electrophilic iminium ion species 2, a compound that has been implicated in the formation of covalent bonds with DNA and possibly other bio macromolecules (Fig. 2). We are also very interested in the biological activities of renieramycin G 11) and cribrostatin 4 (=renieramycin H [12][13][14] ) because both compounds show antiproliferative activity. Renieramycin G and cribrostatin 4 are tetrahydroisoquinolines possessing a C-21 lactam carbonyl group; however, they exhibit low cytotoxicity and are less active than their respective C-21 cyano or carbinolamine containing relatives. To date, five total syntheses of renieramycin G [15][16][17][18][19][20][21] and four total syntheses of cribrostatin 4 22-25) have been published. Several studies on the SAR of renieramycins, including renieramycin G and cribrostatin 4, were conducted, 8,[26][27][28][29][30] but the cytotoxicity profiles of these compounds were not addressed.Among a handful of studies of simple models containing a lactam ring, such as 3, Ong and coworkers reported that pentacyclic scaffold 4 showed low cytotoxicity.31,32) Avendaño and coworkers discovered that pyrazino[1.2-b] isoquinoline-4-one derivative 5 in...

Preparation of Tricyclic Analog as CDE Ring Model of Renieramycin Marine Natural Product by Novel Photo-Induced Transformation of 6-Methoxy-1,2,3,4-Tetrahydroisoquinoline-5,8-dione

“…Compound was obtained as a colorless prisms by recrystallization from MeOH. trans-32: 1 H-NMR (400 MHz, CD3OD) δ: 7.97 (2H, d, J = 7.9 Hz, Bz-H), 7.59 (1H, t, J = 7.9 Hz, Bz-H), 7.45 (2H, t, J = 7.9 Hz, Bz-H), 6.27 (1H, s, 10-H), 6.13 (1H, dd, J = 9.5, 3.8 Hz, 6-H), 4.81-4.86 (1H, 11a-H overlapped with H2O), 4.75 (1H, dd, J = 11.6, 9.5 Hz, 12-H), 4.60 (1H, dd, J = 11.6, 3.8 Hz, 12-H), 4.34 (1H, d, J = 18.0 Hz, 3-H), 4.23 (1H, d, J = 18.0 Hz, 3-H), 3.20 (2H, d, J = 7.3 Hz, 11-H), 2.50 (3H, s, 2-COCH3), 2.06 (3H, s, 8-CH3); 13 C-NMR (100 MHz, CD3OD) δ: 173.2 (s, 2-COCH3), 169.4 (s, C-1), 168.2 (s, C-14), 165.8 (s, C-4), 157.0 (s, C-9), 153.9 (s, C-7), 134.4 (d, Bz), 132.2 (s, Bz), 131.2 (s, C-10a), 130.7 (d, Bz), 129.6 (d, Bz), 111.4 (s, C-6a), 111.4 (s, C-8), 107.9 (d, C-10), 64.5 (t, C-12), 55.7 (d, C-11a), 50.2 (d, C-6), 46.7 (t, C-3), 32.1 (t, C-11), 27.0 (q, 2-COCH3), 8.7 (q, 8-CH3); IR (KBr): 3410, 3391, 1713, 1659, 1273, 1099 cm -1 ; EIMS m/z (%): 438 (M + , 2), 346 (5), 345 (25), 304 (11), 303 (67), 281 (6), 262 (15), 261 (100), 260 (5), 239 (5), 233 (5), 176 (25), 105 (17); HREIMS: calcd for C23H22N2O7 438.1427; found 438.1428. cis-32: mp 243-245 °C (MeOH); 1 H-NMR (400 MHz, CD3OD) δ: 7.87 (2H, br d, J = 7.8 Hz, Bz-H), 7.56 (1H, br t, J = 7.8 Hz, Bz-H), 7.41 (2H, br t, J = 7.8 Hz, Bz-H), 6.35 (1H, s, 10-H), 6.12 (1H, dd, J = 7.9, 4.7 Hz, 6-H), 4.84 (1H, d, J = 16.8 Hz, 3-H), 4.50 (1H, dd, J = 10.9, 7.9 Hz, 12-H), 4.33 (1H, dd, J = 10.9, 4.7 Hz, 12-H), 4.30 (1H, dd, J = 12.1, 5.0 Hz, 11a-H), 3.89 (1H, d, J = 16.8 Hz, 3-H), 3.25 (1H, dd, J = 15.5, 12.1 Hz, 11-H), 3.07 (1H, dd, J = 15.5, 5.0 Hz, 11-H), 2.49 (3H, s, 2-COCH3), 2.07 (3H, s, 8-CH3); 13 C-NMR (100 MHz, CD3OD) δ: 172.4 (s, 2-COCH3), 170.7 (s, C-1), 168.9 (s, C-14), 168.1 (s, C-4), 157.2 (s, C-9), 153.8 (s, C-7), 134.4 (d, Bz), 133.0 (s, C-10a), 131.1 (s, Bz), 130.6 (d, Bz), 129.5 (d, Bz), 112.1 (s, C-6a), 111.4 (s, C-8), 107.5 (d, C-10), 66.6 (t, C-12), 57.8 (d, C-11a), 50.2 (d, C-6), 46.3 (t, C-3), 30.1 (t, C-11), 26.9 (q, 2-COCH3), 8.8 (q, 8-CH3); IR (KBr):3383, 3366, 2924, 1717, 1678, 1368, 1271, 1198, 1099 cm -1 ; EIMS m/z (%): 438 (M + , 1), 346(6), 345(12), 305(14), 304 (54), 303 (100), 263 (5), 262(18), 261 (31), 177(16), 176 (33), 105(13), 77 (5); HREIMS m/z: calcd for C23H22N2O7 438.1427; found 438.1422; Anal. Calcd for C23H22N2O7:C, 63.01; H, 5.06; N, 6.39.…”

Chemistry of Renieramycins. 17. A New Generation of Renieramycins: Hydroquinone 5-O-Monoester Analogues of Renieramycin M as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells

“…20−23 To date, renieramycins A−Y isolated from such sponges have been characterized and become target molecules of interest for synthetic studies 24−37 and biological investigations as the promising anticancer agents. 6,8,9,14,24,34,38 Renieramycin M (1), the most prominent compound in this category, is a bistetrahydroisoquinolinequinone that was isolated as a preeminent alkaloid from the potassium cyanidepretreated methanolic extract of the blue sponge Xestospongia sp., which has been collected in Thailand 13 and the Philippines. 15 Regarding our ongoing research toward the development of new anticancer agents from marine tetrahydroisoquinoline alkaloids, including renieramycins and ectinascidins, the naturally derived renieramycins such as renieramycin M (1), renieramycin E, and renieramycin T (2), a renieramycin− ecteinascidin hybrid structure, showed strong cytotoxicity with IC 50 values in the nanomolar range toward various cancer cell lines, including breast (T47D), colon (HCT116 and DLD1), lung (QG56 and H460), pancreatic (AsPC1), and prostate (DU145) human carcinomas.…”

“…Regarding their structural complexity and diversity, these marine-derived molecules are capable of interacting with numerous biomolecular targets to either inhibit or promote specific biological functions against various types of cancer cell lines. − Renieramycins, marine alkaloids classified into the tetrahydroisoquinoline family, have been isolated from various marine organisms, including sponges in the genera Reniera , , Xestospongia , − Cribrochalina , , and Neopetrosia. Moreover, several renieramycin-type alkaloids have also been obtained from a sponge-eating nudibranch, Jorunna funebris . − To date, renieramycins A–Y isolated from such sponges have been characterized and become target molecules of interest for synthetic studies − and biological investigations as the promising anticancer agents. ,,,,,, Renieramycin M ( 1 ), the most prominent compound in this category, is a bistetrahydro­isoquinolinequinone that was isolated as a preeminent alkaloid from the potassium cyanide-pretreated methanolic extract of the blue sponge Xestospongia sp., which has been collected in Thailand and the Philippines …”

Anti-cancer effects of renieramycin T on human non-small cell lung cancer cells

“…The most prominent compound in this group is renieramycin M isolated from the potassium cyanide pretreated methanolic extract of the blue sponge Xestospongia sp., which has been collected in Thailand and the Philippines [26,27]. Besides from renieramycin M, renieramycins A-Y are isolated from many species of sponges and become target molecules for synthetic studies and biological researches as the anticancer agents [108][109][110][111][112][113][114][115][116][117][118]. Many evidences showed that renieramycins had a strong cytotoxicity against various cancer cells, including breast (T47D), colon (HCT116 and DLD1), lung (QG56 and H460), pancreatic (AsPC1), and prostate (DU145) human carcinomas [23,26,36,114] In 2009, Charupant found that renieramycin M and their derivatives had anti-proliferative activities against breast (MDA-MB-435), and colon (HCT116) cancer cells with a very low IC50 [119].…”