The total synthesis of (-)-jorumycin (1) and (-)-renieramycin G (2) has been accomplished in 25 and 23 steps, respectively, from 5-benzyloxy-2,4-dimethoxy-3-methyl-benzyl alcohol. The synthesis features a substrate-tunable stereoselective intramolecular Pictet-Spengler-type reaction for the construction of the key pentacyclic core of both targets, bearing either the natural configuration or the epimeric configuration at C-3. With access to a C-3 epi-pentacyclic framework, 3-epi-jorumycin (32) and 3-epi-renieramycin G (34) were also successfully synthesized. Furthermore, preliminary biological evaluation of 3-epi-jorumycin (32), in addition to relevant synthetic intermediates, revealed that significant cytotoxicity had been retained in these compounds. Therefore, these early studies constitute the basis for a new structure activity relationship (SAR) investigation for this class of antitumor antibiotics.

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Analogues of the tetrahydroisoquinoline family of antitumor antibiotics, 3-epi-jorumycin (3) and 3-epi-renieramycin G (4) in addition to their respective parent natural products (−)-jorumycin (1) and (−)-renieramycin G (2) were evaluated against both human colon (HCT-116) and human lung (A549) cancer cell lines. (−)-Jorumycin (1) displayed potent growth inhibition with GI 50 values in the low nanomolar range (1.9-24.3 nM), while compounds 2-4 were found to be substantially less cytotoxic (GI 50 0.6-14.0 µM).The tetrahydroisoquinoline family of alkaloids includes potent cytotoxic agents that display a range of biological properties such as antitumor and antimicrobial activities. 1 (−)-Jorumycin (1) (Figure 1), a member of the family, was isolated from the mantle and mucus of the pacific nudibranch Jorunna funebris 2 and is closely related to the saframycins, members of the renieramycin family, and, most notably, Ecteinascidin 743 (Et-743, 5) which was demonstrated to be a highly promising, exceedingly potent antitumor agent currently in phase II/III clinical trials. 3 Consistent with other members in the group, (−)-jorumycin (1) has been shown to harbor potent biological activities. 2,4 Fontana and coworkers, in the context of their original isolation studies, have demonstrated that 1 possesses activity against NIH 3T3 tumor cells (100% of inhibition at 50 ng/mL) in addition to P388, A549, HT29, and MEL28 tumor cell lines (IC 50 12.5 ng/mL). 2 Furthermore, 1 was shown to inhibit the growth of various Gram-positive bacteria (eg. Bacillus subtilis, Staphylococcus aureus) at a concentration lower than 50 ng/mL. 2 Saito and co-workers, employing (−)-jorumycin (1) prepared semisynthetically from renieramycin M, have reported potent antiproliferative activity for 1 against HCT-116 (IC 50 0.57 nM), QG56 (IC 50 0.76 nM), and DU145 (IC 50 0.49 nM) cell lines. 4 (−)-Renieramycin G (2) (Figure 1) was isolated from the marine sponge Xestospongia caycedoi by Davidson in 1992. 5 Despite having an amide carbonyl residue at C-21, 2 was reported to retain cytotoxicity against human cancer cells with MIC values of 0.5 µg/mL and 1.0 µg/mL against KB and LoVo cell lines, respectively. 5 These results are surprising in light of the fact that virtually all biologically active members of this family of tetrahydroisoquinoline alkaloids possess a carbinolamine or cyano function at C-21 that permits the formation of a potent, electrophilic iminium ion species that has been implicated